Process for the preparation of optically active alpha-arylalkanoic acids and novel intermediates thereof

ABSTRACT

Compounds of formula 
&lt;CHEM&gt;
 wherein
 Ar represents an optically substituted aryl group,
 R represents a C1-C4 alkyl;
 R1 and R2, equal to or different from each other, represent hydroxy, O&lt;-&gt;M&lt;+&gt;, OR3 or 
&lt;CHEM&gt;
 R3 represents a C1-C24 alkyl, a C3-C6 cycloalkyl, a phenyl or a benzyl;
 M&lt;+&gt; represents the cation of an alkaline metal;
 R4 and R5, equal to or different from each other,
 represent a hydrogen atom, a C1-C4 alkyl, a C5-C6 cycloalkyl, a (CH2)n-CH2OH group with n=1, 2 or 3, or R4 and R5 together are group (CH2)m  with m=4 or 5, a group -CH2-CH2R6-CH2-CH2- in which R6 is an oxygen atom, an N-H or N-(C1-C4) alkyl group;
 X represents a chlorine, bromine or iodine atom, an hydroxy, acyloxy, alkylsulphonyloxy or arylsulphonyloxy group; the carbon atoms marked by an asterisk are both contemporaneously in the R or S configuration, are described. 
&lt;??&gt;The preparation of the compound of formula I by ketalization or by trans-ketalization with tartaric acid derivatives and their rearrangement into alpha-arylalkanoic acids is described too.

This is a continuation of application Ser. No. 720,380 filed Apr. 5,1985, now patent No. 4,697,036.

The present invention relates to a process for preparing opticallyactive alpha-arylalkanoic acids and the novel intermediates thereof. Inparticular, the present invention concerns an overall enantioselectiveprocess for the preparation of optically active alpha-arylalkanoic acidscomprising two main steps: a stereoselective halogenation of novelchiral (optically active)ketals and a stereoselective rearrangement ofthe thus obtained products.

The alpha-arylakanoic acids constitute a very large class of compounds,of which many have assumed considerable commercial importance inrelatively recent years as anti-inflammatory and analgesic drugs.

These include 2-(4-isobutylphenyl)-propionic acid known as Ibuprofen,2-(3-phenoxyphenyl)-propionic acid known as Fenoprofen,2-(2-fluoro-4-diphenyl)-propionic acid known as Flurbiprofen,2-[4-(2-thienylcarbonyl)-phenyl]-propionic acid known as Suprofen,2-(6-methoxy-2-naphthyl)-propionic acid, of which the (S) isomer isknown as Naproxen, and others.

Another group of alpha-arylalkanoic acids are well known asintermediates in the preparation of pyrethroid insecticides. Theseinclude 2-(4-chlorophenyl)-3-methyl-butyric acid and2-(4-difluoromethoxyphenyl)-3-methyl-butyric acid.

A number of the alpha-arylalkanoic acids exist as a mixture of opticallyactive isomers.

Very often, a decidedly higher biological activity is associated withone enantiomer which thus is much more important than the other from anindustrial viewpoint.

A particularly important example is 2-(6-methoxy-2-naphthyl)-propionicacid, of which the (S) isomer (Naproxen) possesses pharmacologicalproperties which are decidedly better than those of the (R) isomer andof the raceme mixture, so that in practice it is only the (S) isomerwhich is used as pharmaceutical drug.

Of the many methods for synthesis alpha-arylalkanoic acids which haverecently appeared in the literature, the most interesting are thosewhich use rearrangement of aryl-alkyl-ketals which are functionalised onthe alkyl position alpha to the ketal. These include the methodsdescribed in European patent applications 34871 (Blaschim), 35305(Blaschim), 48136 (Sagami), 65394 (Syntex), 89711 (Blaschim), and 101124(Zambon), and in Italian patent applications 21841 A/82 (Blaschim andCNR), 22760 A/82 (Zambon) and 19438 A/84 (Zambon), and in thepublication J. Chem. Soc., Perkin I, 11, 2575 (1982). All theseprocesses lead to recemic mixtures of the two optical isomers.

Optically active alpha-arylalkanoic acids can be prepared by separatingthe enantiomer from the racemic mixture obtained by using the aforesaidprocedures (for example by using optically active bases), or by applyingsome of said rearrangements to optically active ketals, which have beenpreviously prepared and isolated, as described for example in Europeanpatent applications 67698 (Sagami) and 81993 (Syntex).

However, the preparation of optically active ketals as described inthese European patent applications appears rather laborious and costly,and also involves the preparations of intermediates by sophisticatedmethods with low yields, and are not suitable for industrialpreparation.

The resolution of alpha-arylalkanoic acids from the racemic mixture in aconventional way, that is by using optically active bases has thedrawbacks common to all these processes: material costs, manufacturinglabor and equipment for the recovery and racemization of the undesiredoptical isomer.

Therefore, it is important to have a stereoselective process forproducing the desired isomer directly. Such a process obviates thenecessity of subsequently resolving the d- and l-isomers using opticallyactive bases, such as cinchonidine, brucine, alpha-phenylethylamine,N-methyl-glucamine and the like.

The elimination of resolution steps results in a substantial saving,both in material cost and manufacturing labor and equipment. The savingscan be particularly significant with regard to compounds which areapproved for pharmaceutical use as a substantially pure, opticallyactive isomer, such as S(+)2-(6-methoxy-2-naphtyl)-propionic acid(Naproxen) or a precursor thereof which may be easily converted to thisacid.

For the sake of clarity we will state hereinafter the meaning of someterms used in the following specification:

"Chiral" refers to a chemical structure having at least an asymmetrycenter. The configuration of an asymmetric carbon atom is classified as"R" or "S" according to the Cahn-Ingold-Prelog method.

"Enantiomer" or "enantiomorph" refers to a molecule which isnonsuperimposable on its respective mirror image. A necessary andsufficient condition for a molecule to show optical activity (i.e. to bean enantiomer) is that such a molecule not be superimposable with itsmirror image. This phenomenum usually occurs in organic chemistry when acarbon atom is attached to four different atoms or chemical groups."Enantiomer" and "optical isomer" are often used interchangeably in thiscontext.

"Enantiomeric excess" or "e.e." refers to a definition; i.e. thepercentage of the predominant enantiomer minus that of the other. Thus,a mixture of 95% (+) isomer and 5% (-) isomer would have a 90% e.e.

"Optical yield" or "optical purity" may be defined as enantiomericexcess. However, strictly speaking, it refers to the measured rotationshown by the mixture which may or may not reflect the true proportionsof the enantiomers. In this application the two terms are usedinterchangeably.

"Optically active" refers to a system or compound which rotates theplane of polarized light.

"Epimers" are two diastereoisomers which have a different configurationat only one chiral center.

"Diastereoisomers" are stereoisomers that are not mirror images of eachother: they have the same configuration at at least one asymmetriccenter and, at the same time, different configuration at at least oneasymmetric center.

"Diastereotopic" refers to the case in which two atoms or groups in amolecule e.g. CX₂ WY are in such a position that replacing each of themby a group Z leads to diastereoisomers.

"Stereoselective synthesis" refers to any reaction in which one among anumber of stereoisomers is formed exclusively or predominantly.

"Enantioselective synthesis" refers to any reaction in which one of twoenantiomers is formed exclusively or predominantly.

"Racemization" refers to the conversion of the molecules of oneenantiomer into a racemic mixture of both.

We have now prepared and are an object of the present invention, newketals of alkyl-aryl-ketones of formula: ##STR4## in which: Arrepresents aryl, optionally substituted;

R represents linear or branched C₁ -C₄ alkyl;

R₁ and R₂, which can be equal to or different from each other, representa hydroxy, a O⁻ M⁺, OR₃ or NR₄ R₅ group where R₃ is C₁ -C₂₄ alkyl, C₃-C₆ cycloalkyl, phenyl or benzyl; M is the cation of an alkaline metal;

R₄ and R₅, which can be equal to or different from each other, representa hydrogen atom, a C₁ -C₄ alkyl, a C₅ -C₆ cycloalkyl, or --(CH₂)_(n)--CH₂ OH group where n is 1, 2 or 3 or R₄ and R₅ taken togetherconstitute a --(CH₂)_(m) -group where m is 4 or 5 or a --CH₂ --CH₂ --R₇--CH₂ --CH₂ -- group where R₇ is an oxygen atom, a NH group or a C₁ -C₄N-alkyl group; X represents a hydrogen, chlorine, bromine or iodineatom. The carbon atoms indicated by an asterisk are bothcontemporaneously in (R) or (S) configuration. Thus the ketals offormula A are optically active.

The ketals of formula (A) have shown quite unexpected properties whichallow the realization of the new process according to the presentinvention.

In fact, we have found that when ketals of formula A, in which X ishydrogen, are reached with achiral halogenating reagents, achemoselective halogenation occurs in high yield on the diastereotopiccarbon atom in the alpha position with respect to the ketal group and inthe thus obtained alpha halogen ketals (formula A, X=Cl, Br, I) only oneof the epimers is formed or strongly prevails over the other. It isworth noting that the absolute configuration (R,R or S,S) of the chiralcenters already present on the starting ketals A (X=H) is untouched. Asfar as we know, a stereoselective halogenation in the alpha position ofa ketal has never been previously described.

Moreover, we have found that the ketals of formula A in which X=Cl, Br,I provide in high yields alpha-arylalkanoic acids in which theenantiomeric ratio reflects the epimeric ratio of the starting ketalsor, depending on the rearrangement conditions, the acid enantiomericratio is higher than the epimeric ratio of the starting ketals.

To our knowledge, it is the first time that a rearrangment of ketals isdescribed which gives rise to chemically pure alpha-arylalkanoic acidshaving an enantiomeric excess higher than the epimeric excess of thestarting ketals.

Thus a further object of the present invention is an enantioselectiveprocess for the preparation of alpha-aryl-alkanoic acids bydiastereoselective halogenation, in the alpha position to the ketalgroup, of optically active ketals of formula (A) wherein X=H and theenantioselective rearrangement of the obtained halo-ketals into thecorresponding alpha-arylalkanoic acids.

An enantioselective process for preparing optically activealpha-arylalkanoic acids is completely new.

The arylalkanoic acids prepared according to the present invention fallwithin the formula ##STR5## in which R is a C₁ -C₄ alkyl; Ar is asheretofore defined and preferably a monocyclic, polycyclic, ororthocondensed polycyclic aromatic or heteroaromatic group having up to12 carbon atoms in the aromatic system such as phenyl, diphenyl,naphthyl, thienyl, or pyrrolyl. The possible substituents of thesearomatic groups comprise one or more halogen atoms, C₁ -C₄ alkyls, C₃-C₆ cycloalkyls, benzyl, hydroxy, C₁ -C₄ alkoxy, C₁ -C₄ alkylthio, C₁-C₄ haloalkyl, C₁ -C₄ haloalkoxy, phenoxy, thienylcarbonyl and benzoyl.

Specific examples of such substituted aryls are 4-isobutyl-phenyl,3-phenoxy-phenyl, 2-fluoro-4-diphenyl, 4'-fluoro-4-diphenyl,4-(2-thienylcarbonyl)-phenyl, 6-methoxy-2-naphthyl,5-chloro-6-methoxy-2-naphthyl and 5-bromo-6-methoxy-2-naphthyl,4-chlorophenyl, 4-difluoromethoxy-phenyl, 6-hydroxy-2-naphthyl, and5-bromo-6-hydroxy-2-naphthyl.

The ketals of formula (A) which constitute the starting compounds forthe new process according to the present invention are prepared byketalization of a ketone of formula ##STR6## (in which Ar and R have theaforesaid meanings) by means of L(+)-tartaric acid (2R,3R-dihydroxy-butanedioic acid) or D(-)-tartaric acid (2S,3S-dihydroxybutanedioic acid) or derivatives thereof.

The ketones of formula II are products which are known or are easilyprepared by known methods, for example by Friedel-Crafts acylation. Theketalization reaction is carried out according to conventional methods,for example in the presence of an acid catalyst and an orthoester.Alternatively, the water formed during the reaction can be removed byazeotropic distillation, for example with benzene, toluene, xylene,heptane or other suitable solvents. The absolute configuration and theoptical purity of the ketals of formula A in which X is hydrogen are thesame as those of the starting diol (tartaric acid or derivativethereof). Thus, starting from L(+)-tartaric acid, the obtained ketal offormula A has both the carbon atoms marked by an asterisk in formula Ahereabove in the R configuration.

This reaction is particularly suitable for preparing compounds offormuls (A) in which R₁ and R₂ represent a OR₃ group, by reacting theketones of formula (II) with a tartaric acid ester.

The ketals of formula (A) in which R₁ and R₂ are other than OR₃ arepreferably prepared starting from these latter compounds by suitabletransformation of the OR₃ group.

For example, starting from esters of formula (A) in which R₁ and R₂ areOR₃ groups, the corresponding mono-salts (for example R₁ =O⁻ M⁺ and R₂=OR₃) can be prepared by partial saponification with one equivalent of abase (for example alkaline hydroxide), and from these the correspondingmono-acids (for example R₁ =OH, R₂ =OR₃) can be prepared byacidification.

Hydrolysis of the esters with two equivalents of an alkaline base leadsto the formation of the corresponding salts (R₁ =R₂ =O⁻ M⁺) which byacidification produce the free dicarboxylic acids (R₁ =R₂ =OH) which arethe starting compounds for preparing different derivatives such as othermono or di-esters (R₁ and/or R₂ =OR₃) or mono or di-amides (R₁ and/or R₂=NR₄ R₅).

The amides can also be obtained directly from the esters of formula (A)by treatment with a suitable amine of formula R₄ R₅ --N--H.

As stated heretofore, the compounds (A) wherein X=H are useful as thestarting compounds for preparing the compounds of formula (A) in which Xrepresents a chlorine, bromine or iodine atom.

The compounds of formula (A) are halogenated by known halogenatingagents for example bromine, quaternary ammonium perhalides, sulphurylchloride, cupric chloride or bromide, N-bromo or N-chloro-succinimide,N-chloro-phthalimide, pyridine or pyrrolidone perbromide or pyridineperchloride or the analogous iodides, hexachloro-2,4-cyclohexadienone,iodine and iodide chloride, or analogous systems.

We have found that the halogenation of ketals having the carbon atomsmarked by an asterisk in formula A hereabove both in configuration R,that is ketals prepared from L(+)-tartaric acid or a derivative thereof(i.e. the naturally occurring tartaric acid), give rise to the formationof a mixture of epimeric alpha-halo ketals in which the epimer in whichthe carbon atom bonded to the halogen is in the S configuration,strongly prevails. Since the configuration of the carbon atoms marked byan asterisk in formula A hereabove remains unchanged, the major epimerof the alpha halo-ketals derived from the naturally occurring tartaricacid or a derivative thereof, will be hereinafter referred to as RRSepimer and the minor one as RRR epimer.

We have also found that starting from ketals derived from D(-)-tartaricacid, the major epimer has the carbon atom bonded to the halogen atom inthe R configuration.

From the above findings it clearly results that the describedhalogenation reaction is a new stereoselective reaction. The ratiobetween the epimers RRS/RRR is generally higher than 75:25 and in mostof the cases is higher than 94:6. Depending on the substrate and thereaction conditions it is also possible to obtain the RRS epimer as theonly chemically pure alpha-halogen-ketal, the other epimer RRR present,if any, in an amount lower than 1%.

Generally, the yields in alpha-halogen ketals are higher than 90%.

The stereoselectivity of the halogenation reaction is only slightlyaffected by the polarity of the solvent. A number of solvents such ascarbon tetrachloride, 1,2-dichloroethane, chlorobenzene, benzene,toluene, acetonitrile, cyclohexane, ethylacetate, carbon disulphide,acetic acid and so on may be used. Best results are obtained by usingsolvents of low polarity. The reaction may be carried out at roomtemperature with satisfactory results. The stereoselectivity of thehalogenation reaction increases by lowering the reaction temperature.The reaction still occurs up to -70° C.

Preferably, traces of a mineral acid are required to start-up thehalogenation reaction which is usually terminated in a few minutes. Asfar as yields and stereoselectivity are concerned, the preferredhalogenation reation is the bromination. Said reaction is preferablycarried out with bromine as the halogenating agent, at a temperaturebetween -40° and +20° C. in solvents such as carbon tetrachloride,methylene chloride, 1,2-dichloro-ethane and carbon disulphide.

The peculiar characteristics of the ketals of formula A and inparticular the shown high stereoselectivity in the halogenationreaction, were completely unpredictable on the base of the presentknowledge of stereocontrolled reactions. Independently from theaforesaid, the fact that the ketals of formula (A) where X=halogen existin the form of diastereoisomers easily separable by known methods, forexample by fractional crystallization, is also important.

If required, it is therefore possible to separate the desired isomer ofthe ketal of formula (A) and subject this to rearrangement to obtain thealpha-arylalkanoic acid in the substantially pure optically active form.

It is also important to note that tartaric acids and esters, inparticular l(+)-tartaric acid and the relative methyl and ethyl esters,have a commercial cost which is competitive with that of the glycolsdescribed as ketalizing agents in the processes of the known art, andthe preparation of the tartaric acid derivatives (ester, amides, salts)certainly does not constitute a costly process.

The possibility of having groups of different nature in the ketals offormula A, with reference to the substituents R₁ and R₂, enables to varythe hydrophilic and lipophilic properties of said ketals within widelimits, from compounds containing polar grups (alkaline salts, amides)to lipophilic compounds (esters of long-chain alcohols).

This wide possibility of choice allows to select the ketal of formula Amost suitable for the experimental conditions (solvents, temperature,catalysts) used in the various processes for the preparation ofalpha-arylalkanoic acids or their derivatives by rearrangement.

As far as the rearrangement of the ketals of formula A (in which X=Cl,Br, I) is concerned, we have found that the ketals having theconfiguration RRS (wherein S is the configuration of the carbon atombonded to the halogen atom) provide the S-enantiomer of thecorresponding alpha-arylalkanoic acid.

This is particularly important because (a) the S-enantiomer ofalpha-arylakanoic acid is generally the biologically more active isomerand the alpha-arylalkanoic acids present on the market in opticallyactive form are all of S-configuration and because (b) the ketals offormula A having configuration RRS are selectively obtained byhalogenation of the ketals of formula A, X=H in turn easily preparedfrom the appropriate ketone and the naturally occurring L(+)-tartaricacid (or a derivative thereof) which is a really unexpensive material.

In order to conveniently transform the optically active ketals offormula A(X=Cl, Br, I) it is necessary to use a rearrangement methodwhich provides optically active alpha-arylalkanoic acids having anenantiomeric ratio very close to that of the epimers in the startingketals. This implies that the reaction has to be stereospecific and thatthe reaction conditions are such that no racemization occurs in thefinal products. We have found that the known methods provide alphaarylalkanoic acids having enantiomeric ratio equal to or lower than theepimeric ratio of the starting ketals. We have also found, and this is afurther object of the present invention, a new enantioselectiverearrangement method which overcomes the above limits.

Such a process is herewith defined as enantioselective in so far as theenantiomeric composition (ratio between enantiomers S and R) of thealpha-arylalkanoic acids thus obtained, differs from the epimericcomposition of the starting ketals of formula A and more precisely andquite surprisingly corresponds to an increase in the optical purity ofthe alpha-arylalkanoic acid with respect to the epimeric composition ofthe starting ketals.

Thanks to this new, surprising rearrangement process, starting from e.g.a mixture of epimeric ketals of formula A (in which X=Cl, Br, I)sufficiently enriched in the RRS epimer, it is possible to obtain in aoptically pure form the S-enantiomer of the correspondingalpha-arylalkanoic acid.

It is worth noting that the yield of the new rearrangement process is ashigh as 80-90%.

The enantioselective process object of the present invention essentiallyconsists in rearranging a ketal of formula A in which X is a chlorine,bromine or iodine atom, in aqueous medium at an acid pH, at atemperature comprised between room temperature and 100° C.

The above mentioned rearrangement conditions are particularly unexpectedand surprising in that it is well known that the treatment of a ketalwith water under acidic conditions is a general method to convert ketalsinto the corresponding ketones and the alcohol or diol. Accordingly, thepreviously known alpha-haloalkyl-aryl ketals, under the above reactionconditions, undergo a fast hydrolysis providing the corresponding alphahaloalkyl-aryl-ketone and alcohol or diol.

On the contrary, the ketals of formula A object of the presentinvention, when treated in aqueous acid medium, provide in high yieldthe corresponding alpha-arylakanoic acids, ketones being present, ifany, in negligeable amounts.

The rearrangement process object of the invention is preferably carriedout by using ketals of formula A (in which X=Cl, Br, I) soluble or atleast partially soluble in water under the reaction conditions, i.e. theketals of formula A in which R¹ and/or R² are hydrophilic groups.

The rearrangement is preferably carried out by heating the ketal offormula A in water at a pH comprised between 3.5 and 6.5.

The desired pH values may be maintained by adding a suitable amount of abuffer.

The reaction duration depends mainly on the nature of the ketal offormula A, and on the reaction temperature. Generally, a high conversiondegree is reached after some hours.

Usually, the alpha-arylalkanoic acids are scarcely soluble in water,therefore at the end of the reaction the optically activealpha-arylalkanoic acid may be isolated by simple filtration. Apharmaceutical product as pure as required by U.S. Pharmacopeia isobtained by simple acid-base treatment of the product isolated byfiltration. As far as we know, this is the first time that arearrangement of halogenketals for the preparation of alpha-arylalkanoicacids is carried out in water as the only reaction solvent. The mainadvantages of the present rearrangement process from an industrial pointof view, may be summarized as follows: (a) the process isenantioselective and provides alpha-arylakanoic acids in high yields andwith an enantiomeric ratio higher than the epimeric ratio of thestarting ketals; (b) the reaction solvent is water with the consequenteconomic and safety advantages; (c) no metal catalyst is required and(d) the optically active alpha-arylalkanoic acid is separated from thereaction mixture by simple filtration.

By considering the overall process for the preparation of opticallyactive alpha-arylalkanoic acids according to the present invention itmay be said that it consists of two quite new steps: the stereoselectivehalogenation of a ketal of formula A in which X is hydrogen and theenantioselective rearrangement of the thus obtained ketal of formula Ain which X is a chlorine, bromine or iodine atom.

More specifically the overall process for the selective preparation ofthe S-enantiomer of an alpha-arylalkanoic acid according to the presentinvention consists thus of two quite new steps: the stereoselectivehalogenation of the suitable ketal of formula A in which X is hydrogenand in which the carbon atoms marked by an asterisk are both in the Rconfiguration, to selectively obtain the epimer RRS of the ketal offormula A in which X is a chlorine, bromine or iodine atom and theenantioselective rearrangement of the thus obtained ketal in water underacidic conditions.

Such a process is possible thanks to the unexpected characteristics ofthe ketals of formula A shown both in the alpha halogenation step and inthe aqueous rearrangement step.

The rearrangement method may be also performed in different lessadvantageous manners depending on the starting ketal.

For example, the ketals of formula (A) in which X is a iodine atom, whenAr is the 6-methoxy-2-naphthyl group and R is a methyl, can berearranged according to the procedure given in European patentapplication 89711, or by oxidation as described in Italian patentapplication 21841 A/82.

Likewise, the ketals of formula (A) in which X is any halogen atom canbe rearranged in the presence of certain metal salts, as described inEuropean patent applications Nos. 334871 and 35305 and in J. Chem. Soc.,Perkin I, 11, 2575 (1982), or in protic polar medium in neutral orweakly alkaline conditions, optionally in the presence of an inertdiluent, as described in Italian patent application No. 22760 A/82 or inEuropean patent application 101,124.

The latter aforesaid method has important advantages relative inparticular to its ease of industrial realization and to the fact that itdoes not require the presence of metal salts as catalysts. The aforesaidrearrangement reactions lead in general to the formation ofalpha-arylalkanoic acids in the form of their derivative, in particularesters. These are then hydrolysed to the corresponding free acids byconventional methods.

Of the optically active alpha-arylalkanoic acids, the most importantfrom the pharmacological viewpoint is 2-(6-methoxy-2-naphthyl)propionicacid, of which the S(+)isomer is known as Naproxen. In a specificembodiment, the present invention relates to compounds of formula##STR7## (in which R₁ , R₂ and X have the meanings given for the formula(A), Y represents a hydrogen atom or a chlorine or bromine atom and Zrepresents a hydrogen atom, a methyl or an alkaline metal) and their usein the preparation of Naproxen by rearrangement.

The carbon atoms indicated with an asterisk have R configuration andwhen X is different from hydrogen, the carbon atom to which it is bondedhas S configuration.

A compound of formula (B) in which X represents a halogen atom and Z amethyl, may be arranged in the presence of certain metal salts such asAg and Zn, or in a polar solvent under neutral or slightly alkalineconditions.

Moreover a compound of formula (B) in which Z represents an alkalinemetal, may be rearranged in an aqueous or organic medium under neutralor alkaline conditions.

In any case the preferred embodiment according to the present inventionis the rearrangement of the ketals of formula B (in which X=Cl, Br, I)in water, under acidic conditions.

The rearrangement of the epimer RRS of the ketals of formula B leads toS(+)-Naproxen or its direct precursors, for example containing Ysubstituent.

In preparing Naproxen, it is necessary to eliminate the substituent Ywhen this is a chlorine or bromine atom. This is done by hydrogenolysiseither on the alpha-arylalkanoic acid or on the relative ester. Thereaction involving rearrangement of the compounds of formula (A), inparticular when conducted in a medium free from alcohols and glycolsunder mild conditions, can lead to the formation of new intermediateesters of formula ##STR8## (in which Ar, R, R₁ and R₂ have the meaningsgiven for formula A) and R₆ is OH, Cl, Br or I. Depending on thereaction conditions, R₆ can also assume other meanings such as acetate,propionate or benzoate.

Hydrolysis of the compounds of formula (C) then leads to thecorrespoding alpha-arylalkanoic acids.

Likewise, the rearrangement of the compounds of formula (B), whencarried out in a medium free from alcohols and glycols, can lead to theproduction of intermediate esters of formula: ##STR9## (in which R₁, R₂,R₆ and Y have the meanings given for formula (B), and Z represents ahydrogen atom or a methyl), which on hydrolysis form thealpha-arylalkanoic acid known as Naproxen or its immediate precursors.Again in this case, in which the transformation of the halogen ketals toaryl-alkanoic acids takes place in two stages, there is no substantialracemisation, and thus the desired optically active aryl-alkanoic acidis selectively and prevalently obtained.

The compounds of formula (C) are new compounds which constitute afurther object of the present invention, in that they have interestingproperties which make them useful from various aspects. As alreadystated, the compounds of formula (C) form the correspondingalpha-arylalkanoic acids on hydrolysis.

Moreover, because of the presence of the two asymmetric carbon atoms inthe alcoholic moiety (the atoms to which the COR₁ and COR₂ groups arebonded respectively), the esters of formula (C) are useful for theoptical resolution of the alpha-arylalkanoic acids.

The resolution of an acid into its optical isomers is generally carriedout by forming salts with an optically active base. The use of thecompounds (C) constitutes a new process for the resolution of mixturesof optically active alpha-arylalkanoic acids by forming an ester withtartaric acid or one of its derivatives, instead of forming a salt withan optically active base. The use of the compounds of formula (C) forresolving an alpha-arylalkanoic acid is particularly advantageous when,by means of the aforesaid process for rearranging the ketals (A), estersof formula (C) are obtained enriched in the desired isomer.

It is evident that the compounds of formula (C) are useful for theoptical resolution of alpha-arylalkanoic acids independently from themethod of preparation. In this respect, it is possible to prepare thecompounds of formula (C) by esterifying a racemic alpha-arylalkanoicacid (or one which is already rich in one of the two enantiomers)independently from how this has been prepared.

The compounds of formula (D), whether prepared by rearrangement of acompound of formula (B) or prepared by esterifying racemic2-(6-methoxy-2-naphthyl)-propionic acid or one of its immediateprecursors using tartaric acid or one of its derivatives, are useful forseparating, by means of crystallization, the ester of formula (D) whichon hydrolysis produces Naproxen in a substantially pure form.

A further unexpected property of the compounds of formula (C) is thatthey are in themselves pharmacologically active compounds. The compoundsof formula (D) have proved particularly interesting. The followingtables give the data relative to the anti-inflammatory and antipyreticactivity of the compounds (D) in which:

    R.sub.1 =R.sub.2 =OCH.sub.3 ; R.sub.6 =OH; Y=H; Z=CH.sub.3 (a)

    R.sub.1 =R.sub.2 =OCH.sub.3 ; R.sub.6 =OH; Y=Br; Z=CH.sub.3 (b)

compared with Naproxen and with 5-Br Naproxen. (c)

From these data it is evident that the new considered compounds,although having a lesser activity than Naproxen, still have aninteresting activity which could find practical application in humantherapy under determined conditions.

                  TABLE 1                                                         ______________________________________                                        Anti-inflammatory activity of the derivatives (a) and                         (b) with respect to Naproxen and 5-bromo-Naproxen (c)                         by oral administration                                                                  Dose        Inhibition ED.sub.50                                    Compound  μM/kg/os (after 3 h) %                                                                            (L.C. 95%)                                   ______________________________________                                        (a)       10          0          175                                                    30          0          (110-280)                                              100         16                                                      (b)       10          3          160                                                    30          14         (100-250)                                              100         20                                                      (c)       10          6                                                                 30          34                                                                100         34         196                                                    300         56         (120-304)                                    Naproxen  10          38                                                                30          45         31                                                     100         66         (19-49)                                      ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Antipyretic activity of compound (a) and (b) with respect to                  Naproxen and 5-bromo-Naproxen (c) by oral administration in rats              Dose           Change in body temperature (°C.)                        Compound                                                                              μM/kg/oral                                                                            after 1 hour after 2 hours                                 ______________________________________                                        a       10         -0.02        +0.02                                                 30         +0.07        -0.61                                                 100        +0.01        -0.76                                                 300        +0.03        -0.81                                         b       10         -0.17        -0.19                                                 30         -0.49        -0.68                                                 100        -0.46        -0.68                                         c       30         -0.17        -0.66                                                 100        -1.33        -1.67                                                 300        -1.42        -1.84                                         Naproxen                                                                              3          -0.38        -0.52                                                 10         -1.22        -1.48                                                 30         -1.86        -1.89                                         ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        Antipyretic activity of compounds (a) and (b) with respect to                 Naproxen and 5-bromo-Naproxen (c) by peritoneal                               administration in rats                                                                      Change in body temperature (°C.)                                  Dose       after     after after                                     Compound μM/kg/oral                                                                            30 min    1 hour                                                                              4 hours                                   ______________________________________                                        a        10         -0.26     -0.52 -0.19                                              30         -0.61     -1.02 -0.56                                     b        10         -0.24     -0.52 -0.26                                              30         -0.77     -0.87 -0.44                                     c        30         -0.55     -1.01 +0.06                                              100        -0.78     -1.45 -0.99                                     Naproxen 10         -1.00     -1.10 -0.86                                     ______________________________________                                    

Some pratical examples of the process according to the present inventionare described hereinafter in order to illustrate the invention butwithout in any way limiting it.

EXAMPLE 1 Preparation of the compound2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4-(R),5(R)-dicarboxylicacid dimethyl ester

1-(6-methoxy-2-naphthyl)-propan-1-one (46.5 g; 0.217 moles),L(+)tartaric acid dimethyl ester (300 g), trimethyl orthoformate (94 g;0.887 moles) are gradually heated up to complete solution.Methanesulphonic acid (1.48 g; 0.0154 moles) is then added and theobtained solution is refluxed for 2 hours; it is cooled at roomtemperature and the reaction mixture is slowly added to a 10% solutionof Na₂ CO₃ (500 ml). It is extracted with methylene chloride and theorganic extracts are repeatedly washed with water. The organic phase isdried on Na₂ SO₄ and the solvent is evaporated under reduced pressure.

The residue is crystallized from methanol (250 ml).

The desired product is obtained (51.68 g; 0.138 moles; yield 63.6%)having the following characteristics:

m.p.=73°-74° C.

[α]_(D) ²⁰ =+33.04 (c=1%, CHCl₃)

I.R. (Nujol): 1770, 1740 cm⁻¹ (stretching C=O)

NMR (CDCl₃ -TMS, 200 MHz) δ (ppm): 0.94 (t, 3H, J=7, 5 Hz); 2.08 (q, 2H,J=7, 5 Hz); 3.46 (s, 3H); 3.84 (s, 3H); 3.90 (s, 3H); 4.86 (2H, ABq, Δν=10.80, J=6 Hz); 7.1-7.9 (m, 6H).

EXAMPLE 2 Preparation of the mixture of the diastereoisomers of2-(1-bromoethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethylester

To a solution of the compound obtained in Example 1 (37.4 g; 0.1 mole)in 1,2-dichloroethane (100 ml), tetra-n-butylammonium perbromide [N(n.C₄H₉)₄ Br₃ ] (48.2 g; 0.1 mole) is added.

The reaction mixture is kept at 20° C. for 24 h and then slowly addedunder stirring to a 10% solution of Na₂ CO₃ (200 ml). It is extractedwith toluene (2×200 ml) and the combined organic extracts are washedwith a 2% solution of NaHCO₃ (3×100 ml). The organic phase is dried onNa₂ SO₄ and the solvent evaporated under reduced pressure. The crudeproduct obtained (48 g) is purified by chromatography on a silica gelcolumn (eluent hexene:diethylether=75:25) to give 13 g of the desiredmixture of diastereoisomers.

The ratio between the two diastereoisomers (1:2) determined by ¹ H-NMR(200 MHz) is 7:3.

Diastereoisomer 1 (RRS)

¹ H-NMR (CDCl₃ -TMS), δ (ppm): 1.68 (d, 3H, J=7.5 Hz); 3.54 (s, 3H);3.90 (s, 3H); 4.08 (s, 3H); 4.48 (q, 1H, J=7.5 Hz); 4.94 (2H, ABq, Δν=26.8; J=7.2 Hz); 7.1-8.0 (6H, m).

Diastereoisomer 2 (RRR)

¹ H-NMR (CDCl₃ -TMS), δ (ppm): 1.64 (d, 3H, J=7.5 Hz); 3.58 (s, 3H);3.89 (s, 3H); 4.08 (s, 3H); 4.50 (q, 1H, J=7.5 Hz); 4.89 (2H, ABq, Δν=36.3, J=6.3 Hz); 7.1-8.0 (6H, m).

EXAMPLE 3 Preparazione of the2(R)-hydroxy-3(R)-[2-(6-methoxy-2-naphthyl)propanoyl]-butanedioic aciddimethyl ester

A mixture of diastereoisomers 1:2=67:33, obtained according to example 2(5 g; 0.011 moles) dissolved into CH₂ Cl₂ (61 ml) and kept at 0° C.under inert atmosphere is added with silver tetrafluoroborate (2.33 g;0.012 moles). The reaction mixture is kept at 0° C. for 30 minutes andthen the temperature is allowed to raise up to room temperature.

The mixture is filtered and the precipitate washed with CH₂ Cl₂. Theorganic phases are washed with water and dried on Na₂ SO₄. The solventis evaporated under reduced pressure to give a mixture ofdiastereoisomeric esters (ratio determined by NMR, 200 MHz, A:B=64:36).

¹ H-NMR (CDCl₃ -TMS), δ, (ppm-):

Diastereoisomer A (RRS): 1.62 (d, 3H, J=8 Hz); 3.22 (s, 3H); 3.83 (s,3H); 3.92 (s, 3H), 3.21 (d, 1H, J=7.2 Hz); 3.95 (q, 1H, J=8 Hz); 4.68(dd, 1H, J_(CH-OH) =7.2 Hz, J_(CH-CH) =2.47 Hz); 5.37 (d, 1H, J=2.47Hz); 7.1-7.8 (6H, aromatic protons.

Diastereoisomer B (RRR): 1.66 (d, 3H, J=8 Hz); 3.58 (s, 3H); 3.72 (s,3H); 3.92 (s, 3H); 3.24 (d, 1H, J=7.6 Hz); 3.97 (q, 1H, J=8 Hz), 4.78(dd, 1H, J_(CH-OH) =7.6 Hz, J_(CH-CH) =2.47 Hz); 5.45 (d, 1H, J=2.47Hz); 7.1-7.8 (6H, aromatic protons).

EXAMPLE 4 Preparation of 2-(6-methoxy-2-naphthyl) propionic acid

A mixture of diastereoisomer esters A and B prepared as described inExample 3 (ratio A:B=62.38) (3.2 g) dimethoxyethane (24 ml),hydrochloric acid 12N (24 ml) is kept under stirring, at 95° C. for 2.5h. It is cooled to room temperature, poured into water and extractedwith CH₂ Cl₂.

The combined organic extracts are washed with a saturated solution ofsodium bicarbonate

The aqueous phase is acidified to give the2-(6-methoxy-2-naphthyl)propionic acid (1.3 g).

An analitically pure sample obtained by column chromatography on silicagel (eluent hexene:diethylether=1:1), with [α]_(D) ²⁰ =+12.9° (c=1%,CHCl₃) is esterified with diazomethane. The obtained methyl ester isanalyzed by ¹ H-NMR (200 MHz) using an optically active shift agent(Europium (III)-tris-[3-(eptafluoropropylhydroxymethylene)-d-camphorate]in CDCl₃).

The enantiomeric ratio is (+)S:(-)R=62:38.

EXAMPLE 5 Preparation of the 2-(6-methoxy-2-naphthyl)-propionic acid

A mixture of diastereoisomeric ketals prepared as described in Example2, in a ratio of 1:2=67:33, is heated at 125° C. in ethylene glycol, inthe presence of potassium acetate for 20 h. After work up of thereaction mixture, a mixture of esters if obtained that are hydrolyzed asdescribed in Example 4. The (+)(S)-2-(6-methoxy-2-naphthyl) propionicacid (Naproxen) is obtained, with an optical purity of 40%;m.p.=151°-152° C.

EXAMPLE 6 Preparation of the diastereoisomeric mixture of the compound2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester

To a solution of2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester (3.74 g; 0.01 moles) in CCl₄ (70 ml) kept at 0° C.under inert atmosphere, a solution of bromine (3.2 g; 0.02 moles) inCCl₄ (7 ml) cooled at 0° C. is added dropwise in 1 h.

The mixture is kept at 0° C. for two hours, then poured under vigorousstirring into an 10% aqueous solution of Na₂ CO₃ (250 ml) and extractedwith CH₂ Cl₂ (3×50 ml). The combined organic extracts are dried on Na₂SO₄ and the solvent evaporated under vacuum. The residue (5 g; 0.0093moles; yield 93%) consists of a mixture of the two diastereoisomersidentified with 3 and 4.

The ratio between the diastereoisomers 3:4, determined by HPLC and ¹H-NMR, is 95:5.

The major isomer has the same configuration (S) of the diastereoisomer 1described in Example 2, refererring to the aliphatic carbon atom bondedto bromine.

Diastereoisomer 3 (RRS)

¹ H-NMR (200 MHz) (CDCl₃ -TMS), δ (ppm): 1.66 (d, 3H, J=6.8 Hz); 3.52(s, 3H); 3.88 (s, 3H); 4.05 (s, 3H); 4.46 (q, 1H, J=6.8 Hz); 4.94 (2H,ABq, J=6 Hz); 7.28-8.24 (5H, aromatic protons).

Diastereoisomer 4 (RRR)

¹ H-NMR (200 MHz) (CDCl₃ -TMS), δ (ppm): 1.63 (d, 3H, J=6.8 Hz); 3.56(s, 3H); 3.87 (s, 3H); 4.05 (s, 3H); 4.48 (q, 1H, J=6.8 Hz); 4.91 (2H,ABq, J=6 Hz); 7.28-8.24 (5H, aromatic protons).

The HPLC analysis (high pressure liquid chromatography) has beenperformed under the following conditions: Hewlett Packard instrumentmod. 1084/B with variable wavelength UV detector:

Analytical conditions:

Column BRAWNLEE LABS RP8 (5μ) spheri 250 mm×4.6 mm (internal diameter)

Solvent A: bidistilled water, flow 0.9 ml/min

Solvent B: methanol, flow 1.1 ml/min

Solvent A temperature: 60° C.

Solvent B temperature: 40° C.

Column temperature: 50° C.

Wavelength (λ): 254 nanometers

Injection: 10 μl of a solution containing 3 mg/ml of a sample inacetonitrile.

Retention times: Diastereoisomer 3: 18.20 min, Diastereoisomer 4: 19.90min.

A mixture of diastereoisomers 3 and 4 in ratio 95:5 obtained as abovedescribed is chromatographed on silica gel, by using as eluent a mixtureof diethylether:hexane=3:7. The collected fractions are separatelyanalyzed by HPLC. The fractions containing the diastereoisomer 3 showinga diastereoisomeric purity higher than 99% are collected.

The solvent is evaporated under vacuum to give the pure diastereoisomer3.

¹ H-NMR (200 MHz) (CDCl₃ -TMS) delta (ppm): 1.66 (d, 3H, J=7.5 Hz); 3.52(s, 3H); 3.88 (s, 3H); 4.05 (s, 3H); 4.46 (q, 1H, J=7.5 Hz); 4.94 (2H,ABq, J=7.2 Hz); 7.28-8.24 (5H, aromatic protons).

EXAMPLE 7 Preparation of a mixture of diastereoisomers of the compound2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester

The reaction described in Example 6 has been repeated with differentsolvents and at different temperatures according to the followingprocedure.

To a solution of2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester (0.01 moles) in the solvent indicated in thefollowing Table (70 ml), kept under inert atmosphere at the temperaturealso indicated in the Table, a solution of bromine (0.02 moles) in thesame solvent (7.0 ml), pre-cooled to the temperature of the abovemixture, is added. The so obtained reaction mixture is kept at thetemperature indicated to reach a substantially complete conversion. Itis then worked up as described in Example 6. The ratio between thediastereoisomers 3 and 4 is indicated in the Table.

                  TABLE                                                           ______________________________________                                                                      Ratio                                                              T          diast. 3                                        Solvent            (°C.)                                                                             diast. 4                                        ______________________________________                                        Carbon tetrachloride                                                                             20         93/7                                            1,2-Dichloroethane 20         93/7                                            1,2-Dichloroethane 0          91/9                                            1,2-Dichloroethane -30        92/8                                            1,1,2,2-Tetrachloroethane                                                                        20         89/11                                           Chlorobenzene      20         90/10                                           Benzene            20         91/9                                            Benzene            0          92/8                                            Toluene            20         91/9                                            Ethylenglycoldimethylether                                                                       20         86/14                                           Acetonitrile       20         82/18                                           Cyclohexane        20         88/12                                           Orthodichlorobenzene                                                                             20         89.2/10.8                                       Sulfolane          27         78/22                                           Ethylacetate       20         91/9                                            Para-dichlorobenzene                                                                             60         87/13                                           Carbondisulfide    15         92.3/7.7                                        Acetic acid        15         89/11                                           Hexafluorobenzene  15         90.3/9.7                                        Molar yield 90-95%                                                            ______________________________________                                    

EXAMPLE 8 Preparation of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethylester

To a solution of2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester (70 g; 0.187 moles) in 1,2-dichloroethane (175 ml)kept at -30° C., under inert atmosphere and under stirring, a brominesolution (59.8 g; 0.374 moles) in 1,2-dichloroethane (140 ml) is addedin 2 h. The reaction mixture is kept at -30° C. up to a completeconversion of the starting product, then is added slowly dropwise to a10% solution of Na₂ CO₃ (1000 ml) under vigorous stirring.

The organic phase is separated, washed with water, dried on Na₂ SO₄ andthe solvent evaporated under vacuum. The mixture of the twodiastereoisomers 3:4 is obtained in a ratio 9:1. The above ratio hasbeen determined by HPLC and ¹ H-NMR.

EXAMPLE 9 Preparation of2(R)-hydroxy-3(R)-[2-(5-bromo-6-methoxy-2-naphthyl)propanoyl]-butanedioicacid dimethylester

To a solution of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester (2.66 g; 0.005 moles; ratio diastereoisomer 3 todiastereoisomer 4=85:15 determined by HPLC) in 1,2-dichloroethane (20ml), kept under stirring at -15° C. under inert atmosphere, silvertetrafluoroborate (1.17 g 0.006 moles) is added.

The reaction mixture is kept at -15° C. for 2 h, then allowed to reachroom temperature in about 1 h and filtered. The organic phase is washedwith water, dried on Na₂ SO₄ and the solvent evaporated under vacuum.

The desired product is obtained (2.2 g; 0.0047 moles; yield 94%) as amixture of two diastereoisomers named C and D, in a ratio C:D=84:16determined by ¹ H-NMR, 200 MHz.

¹ H-NMR (CDCl₃ -TMS)

Diastereoisomer C (RRS)--The data are consisting with the givenstructure; the data which refer to the aliphatic part are analogous tothose of the diastereoisomer A described in Example 3.

Diastereoisomer D (RRR)--The data are quite consisting with the givenstructure; the data which refer to the aliphatic part are analogous tothose of diastereoisomer B described in Example 3.

The diastereoisomer C has been separated in pure form by crystallizationfrom methanol. M.p.=124°-126° C.; [α]_(D) ²⁰ =+60.2 (c=1% in CHCl₃).

EXAMPLE 10 Preparation ofS(+)-2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid

(a) a mixture of:

2(R)-hydroxy-3(R)-[2-(5-bromo-6-methoxy-2-naphthyl-propanoyl]butanedioicacid dimethyl ester (diastereoisomer C of Example 9; 0.5 g; 1.065mmoles)

sodium hydroxide (0.170 g; 4.26 mmoles)

water (2.5 ml)

methanol (3.5 ml)

is kept under stirring at room temperature for 18 hours. The mixture isdiluted with water and extracted with dichloromethane. The aqueous phaseis acidified with conc. HCl and extracted with dichloromethane. Theorganic phase is then washed with water, dried and the solventevaporated under vacuum. The so obtained crude acid is purified bychromatography on silica gel (eluent hexene:diethylether=8:2).

The S(+)-2-(5-bromo-6-methoxy-2-naphthyl)-propionic in the pure form isobtained; m.p.=155°-157° C.; [α]₅₇₈ ²⁰ =+20.5 (c=0.5% in CHCl₃).Starting from this acid, by debromination according to the methoddescribed in the Belgian Patent 892.689, Naproxen is obtained having thesame optical purity of the starting 5-Bromo derivative.

(b) a mixture of:

2(R)-hydroxy-3(R)-[2-(5-bromo-6-methoxy-2-naphthyl)-propanoyl]-butanedioicacid dimethyl ether (diastereoisomer C obtained according to Example 9;0.2 g; 0.426 mmoles)

1,2-dimethoxy-ethane (3 ml)

conc. HCl (3 ml)

is kept at 95° C. for 2 h. The reaction mixture is then cooled to roomtemperature, diluted with water and extracted with CH₂ Cl₂. The organicphase is washed with water and extracted with 10% sodium bicarbonate.

The basic aqueous extract is acidified with conc. HCl and extracted withCH₂ Cl₂.

The organic extract is washed with water, dried on Na₂ SO₄ and thesolvent evaporated under reduced pressure.

The optically pure S(+)-2-(5-bromo-6-methoxy-2-naphthyl)-propionic acidis obtained:

[α]₅₇₈ ²⁰ =+44.9 (c=0.5% in CHCl₃).

This acid is debrominated to give Naproxen having the same opticalpurity, following the procedure described in the Belgian Patent 892.689:[α]_(D) ²⁰ =+66° (c=1% in CHCl₃).

EXAMPLE 11 Preparation of the 2-(5-bromo-6-methoxy-2-naphthyl) propionicacid

A mixture of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester prepared according to Example 8 (2.66 g; 5 mmoles;diaster.3:diaster.4=9:1 as determined by HPLC), sodium bicarbonate (1.7g; 20 mmole) and water is refluxed for 22 h. The reaction mixture iscooled to room temperature and extracted with diethylether. The aqueousphase is acidified with conc.HCl and the precipitate filtered and washedwith water.

The so obtained crude acid (1.13 g) is purified on a silica gel column(eluent hexane:diethylether in ratio 8:2).

The 2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (0.92 g; 3 mmoles;yield 60%) is obtained--m.p.=156°-158° C.; [α]₅₇₈ ²⁰ =+23.5 (c=0.5% inCHCl₃).

EXAMPLE 12 Preparation of2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid diethyl ether.

1-(6-methoxy-2-naphthyl)-propan-1-one (20.0 g; 0.093 moles), diethylester of L(+)tartaric acid (160 g) and triethyl orthoformate (37 g; 0.25moles) are slowly heated up to complete solution. Methanesulphonic acid(0.68 g; 0.007 moles) is added and the solution is refluxed for 1 h.

The reaction mixture is cooled to room temperature and added to a 10%solution of Na₂ CO₃ (250 ml) under vigorous stirring. It is extractedwith CH₂ Cl₂ and the organic extracts are repeatedly washed with water.

The organic phase is dried on Na₂ SO₄ and the solvent is evaportatedunder reduced pressure.

The crude product is gradually heated up to 180° C. (external bath)under a pressure of 0.1 mmHg.

The desired product is obtained (33.6 g; 0.084 moles; yield 90%) havingthe following characteristics:

[α]_(D) ²⁰ =+20.59° (c=1%, CHCl₃)

I.R. (NEAT): 1770, 1740 cm⁻¹ (stretching C=O)

¹ H-NMR (CDCl₃ -TMS) δ (ppm): 0.95 (t, 3H, J=6.4 Hz); 1.02 (t, 3H, J=7.3Hz); 1.3 (t, 3H, J=7.3 Hz); 2.08 (q, 2H, J=6.4 Hz); 3.9 (s, 3H); 3.88(dq, 2H, J=11 Hz, J=7.3 Hz); 4.30 (q, 2H, J=7.3 Hz); 4.82 (ABq, 2H,J=5.94 Hz); 7-8 (6H, aromatic protons).

EXAMPLE 13 Preparation of the diastereoisomers mixture of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid diethyl ester

To a solution of2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid diethyl ester (2 g; 0.005 moles) in CCl₄ (35 ml) is added asolution of bromine (1.6 g; 0.01 moles) in CCl₄ (3.5 ml), under inertatmosphere, at 20° C.

The mixture is kept at 20° C. for two hours and then worked up asdescribed in Example 6.

The desired diastereoisomeric mixture is obtained (named as 5 and 6) in93% yield.

The ratio between the diastereoisomers, determined by HPLC, is5:6=91.5:8.5.

The diastereoisomer 5 (which is the prevalent one) shows the sameconfiguration (S) of the diastereoisomer 1 (Example 2) and ofdiastereoisomer 3 (Example 6) with respect to the aliphatic carbon atombonded to bromine.

¹ H-NMR (CDCl₃ -TMS) (200 MHz)

Diastereoisomer 5 (RRS): δ (ppm) 1.04 (t, 3H, J=7 Hz); 1.31 (t, 3H, J=7Hz); 1.65 (d, 3H, J=6.8 Hz); 3.92 (dq, 2H, J=11.3 Hz, J=7 Hz); 3.98 (s,3H); 4.3 (q, 2H, J=7 Hz); 4.48 (q, 1H, J=6.8 Hz); 4.88 (ABq, 2H, J=6.5Hz); 7.2-8.2 (5H, aromatic protons).

Diastereoisomer 6 (RRR): δ (ppm) 1.09 (t, 3H, J=7 Hz); 1.29 (t, 3H, J=7Hz); 1.62 (d, 3H, J=6.8 Hz); 3.98 (s, 3H); 4.29 (q, 2H, J=7 Hz); 4.85(ABq, 2H, J=6.5 Hz); 7.2-8.2 (5H, aromatic protons).

HPLC analysis performed under essentially the same conditions asdescribed in Example 6, with the only difference that the percentage ofthe solvent B is 58% (total flow 2 ml/min). Diastereoisomer 5: retentiontime 24.03 minutes. Diastereoisomer 6: retention time 25.00 minutes.

EXAMPLE 14 Preparation of2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylicacid

A mixture of 2-ethyl-2-(6-methoxy-2-naphthyl) 1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester (4.68 g; 12.5 mmoles), NaOH (1 g,25 mmoles) and water (50 ml) is kept under stirring at room temperaturefor 5 h. The reaction mixture is filtered and the aqueous phaseacidified with conc. HCl to pH 1. It is then extracted with diethyletherand the combined organic amyl extracts are washed with water and driedon Na₂ SO₄. Evaporation of the solvent under vacuum gives2-ethyl-2-(-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylicacid (3.46 g; 10 mmoles); yield 80%), m.p.=100°-102° C.

¹ H NMR (200 MHz) (CDCl₃ -TMS) delta (ppm): 0.92 (t, 3H, J=7 Hz); 2.07(q, 2H, J=7 Hz); 3.86 (s, 3H); 4.78 (2H, ABq Δν=4.2; J=5.8 Hz); 7,0-8,0(6H, aromatic protons). A sample esterified with diazomethane indiethylether gives the starting methyl ester with unchanged ¹ HNMR,I.R., m.p., and [α].

EXAMPLE 15 Preparation of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid

A mixture consisting of the two diastereoisomers of2-(1-bromo-ethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester, in ratio 9:1 (6.65 g; 12.5mmoles), NaOH (1 g; 25 mmoles), dimethoxyethane (10 ml) and water (10ml) is kept under stirring at room temperature for 2 h.

The reaction mixture is diluted with water and extracted withdiethylether.

The aqueous phase is then acidified to pH 1 with conc. HCl and extractedwith diethylether.

The combined organic extracts are washed with water and dried on Na₂SO₄.

The evaporation of the solvent under vacuum leads to the twodiastereoisomers of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid (5.8 g; 11.5 mmoles; yield 92%) named with thenumbers 7 and 8. The ratio between the diastereoisomers 7 and 8,determined by ¹ HNMR (200 MHz), is of 9:1.

Diastereoisomer 7 (RRS) (CDCl₃ -TMS) delta (ppm): 1.60 (d, 3H, J=7 Hz);4.00 (s, 3H); 4.49 (q, 1H, J=7 Hz); 4.87 (2H, ABq, Δν=18.9; J=6.5 Hz):7.2-8.2 (5H, aromatic protons).

EXAMPLE 16 Preparation of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid

A mixture of2-[1(S)bromoethyl]-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester (diastereoisomer 3 in the pureform; 6.65 g; 12.5 mmoles), NaOH (1 g; 25 mmoles), dimethoxyethane (10ml) and water (10 ml) is kept under stirring at room temperature for 2h.

The reaction mixture is diluted with water and extracted withdiethylether. Then the aqueous phase is acidified at pH 1 with conc. HCland extracted with diethylether.

The combined organic extracts are washed with water and dried on Na₂SO₄. Evaporating of the solvent under vacuum gives2-[1(S)-bromoethyl]-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid (diastereoisomer 7)

¹ H NMR (200 MHz) CDCl₃ -TMS) delta (ppm): 1.60 (d, 3H, J=7 Hz); 4.00(s, 3H); 4.49 (q, 1H, J=7 Hz); 4.87 (2H, ABq, Δν=18.9; J=6 Hz); 7.2-8.2(5H, aromatic protons).

EXAMPLE 17 Preparation of2(R)-hydroxy-3(R)-[2-(5-bromo-6-methoxy-2-naphthyl)propanoil]-butanedioicacid dimethyl ester

To a mixture of the diastereoisomers 3 and 4 in ratio 94:6 (determinedby HPLC) (10.0 g; 0.0188 moles) in 1,2-dichloroethane (75 ml) kept understirring at +15° C., under inert atmosphere, a solution of silvertetrafluoborate (4.4 g; 0.0226 moles) in 1,2-dichloroethane (30 ml), isadded in 15 min.

The reaction mixture is kept at +15° C. for 7 h, poured slowly intocooled water (100 ml) in such a manner that the temperature does notovercome +10° C. The mixture is then filtered on Celite and the filtratewashed with CH₂ Cl₂ (100 ml).

The organic phase is washed with water (2×200 ml) and dried on Na₂ SO₄.Evaporating of the solvent under reduced pressure gives a residue (7.2g; 0.0154 moles; yield 82%) consisting of a mixture of diastereoisomericesters (ratio diast. C:D=91:9, determined by ¹ H NMR analysis).

EXAMPLE 18 Preparation of the compound2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylicacid diisopropyl ester

1-(6-methoxy-2-naphthyl)-propan-1-one (10.3 g; 0.048 moles),di-isopropyl ester of L(+) tartaric acid (94 g) and trimethylorthoformate (7.57 g; 0.071 moles), are gradually heated up to completesolution. It is then added methanesulphonic acid (0.37 g; 0.0039 moles)and the solution is refluxed for 2.5 h (temperature of the solution 90°C.). The reaction mixture is cooled and slowly added to a 10% solutionof Na₂ CO₃ (100 ml), under vigorous stirring.

It is extracted with CH₂ Cl₂ and the organic extracts are washed withwater (100 ml).

The organic phase is dried on Na₂ SO₄ and the solvent is evaporatedunder reduced pressure to give 94 g of crude product. The crude productis then slowly heated up to 220° C. (external bath) at 0.2-0.3 mm/Hg.The residue is purified by cromatography on a silica gel column (eluenthexene: diethyl- ether=85:15)2-ethyl-2(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R) dicarboxylicacid diisopropylester (14.2g; 0.033 moles; yield 69%) was obtained.

I.R. (Neat): 1770, 1740 cm⁻¹ (stretching C=O) ¹ H NMR (CDCI₃ -TMS) (200MHz) delta (ppm): 0.95 (t, 3H, J=7.6 Hz); 0.96 (d, 3H, J=6.4 Hz); 1.05(d, 3H, J=6.4 Hz); 1.29 (d, 6H, J=6.4 Hz); 3.8 (s, 3H); 4.75 (ABq, 2H,J=6.6 Hz); 4.79 (q, 1H, J=6.4); 5.14 (ept., 1H, J=6.4); 7-8 (m, 6H).

EXAMPLE 19 Preparation of the diastereoisomeric mixture of the2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid diisopropylester

A solution of bromine (16 g; 0.01 moles) in CCl₄ (3.5 ml) is addeddropwise, at 15° C., under inert atmosphere, in 1 h to a solution of2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylicacid diisopropyl ester (2.15 g; 0.005 moles) in CCl₄ (35 ml). Themixture is kept at 15° C. for 2 h and then worked up as described inexample 6. The desired diastereoisomers mixture (isomeric 9 and 10) isobtained in a 94% yield. The ratio between the two diastereoisomers asdetermined by HPLC is 9:10=93.9:6.1. ¹ H NMR (CDCl₃ -TMS) (200 MHz)

Diastereoisomer 9 (RRS): delta (ppm): 0.96 (d, 3H, J=6.4 Hz); 1.06 (d,3H, J=6.4 Hz); 1.3 (d, 6H, J=6.4 Hz); 1.67 (d, 3H, J=7.2 Hz); 3.98 (s,3H); 4.47 (q, 1H, J=7.2 Hz); 4.80(ABq, 2H, J=6.6 Hz); 4.80(m, 1H, J=6.4Hz); 5.15 (m, 1H, J=6.4 Hz); 7.2-8.2 (5H, aromatic protons).

Diastereoisomer 10 (RRS): delta (ppm): 0.96 (d, 3H, J=6.4 Hz); 1.06 (d,3H, J=6.4 Hz); 1.28 (d, 6H, J=6.4 Hz); 1.63 (d, 3H, J=7.2 Hz); 3.98 (s,3H); 4.47 (q, 1H, J=7.2 Hz); 4.80 (ABq, 2H, J=6.6 Hz); 4.80(m, 1H, J=6.4Hz); 5.15 (m, 1H, J=6.4 Hz); 7.2-8.2 (5H, aromatic protons).

HPLC analysis performed as described in ex. 6, with the only differencethat the percentage of solvent B is 62.5% (total flow 2 ml/min.)Diastereoisomer 9:retention time 23.68 min. Diastereoisomer 10:retentiontime 24.46 min.

EXAMPLE 20 Preparation of2(R)hydroxy-3(R)-[2-(5-bromo-6-methoxy-2-naphthy)-propanoyl]-butanedioicacid diisopropylester

Following the procedure described in ex. 17 a mixture ofdiastereoisomeric ketals 9 and 10 (ex. 19) in a ratio 9:10=94:6determined by HPLC (2.0 g; 3.4 mmoles), a residue is obtained (1.6 g)that after purification by chromatography on silica gel column (eluenthexene:diethylether =1:1) give a mixture of diastereiosomers esters (Eand F) in ratio 90:10 (determined by ¹ H NMR (200 MHz) analysis) ¹ H-NMR(CDCl₃ -TMS) (200 MHz)

Diastereoisomer E (RRS): delta (ppm): 0.55 (d, 3H, J=6.12 Hz); 1.02 (d,3H, J=6.12 Hz); 1.24 (d, 3H, J=6.12 Hz); 1.27 (d, 3H, J=6.12 Hz); 1.61(d, 3H, J=7 Hz); 3.17 (d, 1H, J=6.8 Hz); 4.00 (q, 1H, J=7 Hz); 4.02 (s,3H); 4.52 (ept, 1H, J=6.12 Hz); 4.62 (dd, 1H, J_(CH-CH) =2.2 Hz,J_(CH-OH) =6.8 Hz); 5.13 (ept, 1H, J=6.12 Hz); 5.30 (d, 1H, J=2.2 Hz);7.2-8.2 (5H, aromatic system).

Diastereoisomer F (RRR): delta (ppm): 0.95 (d, 3H, J=6.12 Hz); 1.12 (d,3H, J=6.12 Hz); 1.14 (d, 3H, J=6.12 Hz); 1.19 (d, 3H, J=6.12 Hz); 1.62(d, 3H, J=7 Hz); 3.17 (d, 1H, J=6.8 Hz); 4.00 (q, 1H, J=7 Hz); 4.02 (s,3H); 4.52 (ept, 1H, J=6.12 Hz); 4.62 (dd, 1H, J_(CH-CH) =2.2 Hz, J_(CH-)OH=6.8 Hz); 5.13 (ept, 1H, J=6.12 Hz); 5.41 (d, 1H, J=2.2 Hz); 7.2-8.2(5H, aromatic system).

EXAMPLE 21 Preparation of the 2-(5-bromo-6-methoxy-2-naphthyl)-propionicacid

A mixture of diastereoisomers E and F (ex. 20) in a ratio E:F=90:10(0.35 g; 0.648 mmoles), dimethoxyethane (4.6 ml) and 12N HCl (4.6 ml) iskept at 88° C. under stirring for 2 h. It is cooled to room temperatureand then it is worked up as described in ex. 10(b). The so obtainedcrude product is eluted through a silica gel column (eluent hexene:ethylether=8:2), to give the 2-(5-bromo-6-methoxy-2-naphthyl)propionic acid:m.p.=148°-151° C.; [α]₅₇₈ ²⁰ =+38° (c=0.5% CHCl₃).

The methylester of the above acid obtained by esterification withdiazomethane, analyzed by ¹ H-NMR (200 MHz) using optically active shiftagent (europium (III)tris-[3-(eptafluoropropylhydroxymethylene)-d-camphorate] in CDCl₃, showsa ratio between the enantiomers of S(+):R(-)=90:10.

EXAMPLE 22 Preparation of2(R)hydroxy-3(R)-[2-(5-bromo-6-methoxy-2-naphthyl)propanoyl]-butanedioicacid diethylester

Following the procedure as described in ex. 17 a mixture ofdiastereoisomeric ketals 5 and 6 (ex. 13) having a ratio 5:6=93:7,determined by HPLC, (2.41 g; 4.3 mmoles), a residue is obtained (1.95 g)that by elution through a silica gel column (eluenthexane:diethylether=1:1) gives a mixture of diastereoisomeric estersnamed as G and H (1.77 g; 3.6 mmoles; yield 83%) in ratio G:H=86:14determined by ¹ H-NMR, 200 MHz. ¹ H-NMR (CDCl₃ -TMS) (200 MHz):

Diastereoisomer G (RRS): delta (ppm): 0.76 (t, 3H, J=7.2 Hz); 1.27 (t,3H, J=7.2 Hz); 1.58 (d, 3H, J=7 Hz); 3.10(d, 1H, J=7.12 Hz); 3.58 (q diAB, 2H, J_(gem) =12 Hz, J=7.2 Hz); 4 (q, 1H, J=7 Hz); 4.01 (s, 3H); 4.27(q, 2H, J=7.2 Hz); 4.65 (dd, 1H, J_(CH-OH) =7.12 Hz); J_(CH-OH) =2.4Hz); 5.32 (d, 1H, J=2.4 Hz); 7.2-8.2 (5H, aromatic protons).

Diastereoisomer H (RRR): delta (ppm): 1.08 (t, 3H, J=7.2 Hz); 1.14 (t,3H, J=7.2 Hz); 1.62 (d, 3H, J=7 Hz); 3.1 (d, 1H, J=7.12 Hz); 3.58 (q diAB, 2H, Jgem=12 Hz, J=7.2 Hz); 4.00 (q, 1H, J=7 Hz) 4.01 (s, 3H); 4.27(q, 2H, J=7.2 Hz); 4.65 (dd, 1H, J_(CH-OH) =7.12 Hz; J_(CH-CH) ==2.4Hz); 5.44 (d, 1H, J=2.4 Hz); 7.2-8.2 (5H, aromatic protons).

EXAMPLE 23

A mixture of diastereoisomeric esters G and H prepared as described inex. 22 (ratio G:H=86:14) (0.64 g; 1.28 mmoles), dimethoxyethane (9 ml)and 12N HCl (9 ml) is kept at 95° C. (temperature of the bath) understirring for 1 h. It is cooled to room temperature and then it is workedup as described in ex. 10(b). The so obtained crude acid is elutedthrough a silica gel column (eluent hexane: diethylether=1:1). The2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid is obtained.M.p.=149°-151° C. and [α]₅₇₈ ²⁰ =+33.94° (c=0.5%, CHCl₃).

A sample is esterified with diazomethane and the obtained methylester isanalysed with ¹ H-NMR (200M Hz) using an optically active shift agent(europium (III) tris [3-(eptafluoropropylhydroxymethylene)-d-camphorate]in CDCl₃ The enantiomers ratio isS(+):R(-)=86:14.

EXAMPLE 24 Preparation of2-ethyl-2-(6-methoxy-2-naphthy)-1.3-dioxolane-4(S), 5(S)-dicarboxylicacid dimethylester

1-(6-methoxy-2-naphthyl)-propan-1-one (20 g; 0.093 moles), dimethylesterof D(-)tartaric acid (129 g) and trimethyl orthoformate (29 g; 0.27moles) are gradually heated up to a complete solution. It is then addedmethanesulphonic acid (0.74 g; 7.7 mmoles) and the solution is refluxed(84° C.) for 1 h; it is cooled to room temperature and the mixture ispoured slowly in a 10% solution of Na₂ CO₃ (250 ml) under vigorousstirring. The mixture is extracted with CH₂ Cl₂ (250 ml) and the organicextracts are washed with water. The organic phase is dried on Na₂ SO₄and the solvent is evaporated under reduced pressure. The crude product(40.3 g) is gradually heated up to 180° C. at 0.1-0.5 mm/Hg, understirring. The residue (33.3 g) is crystallized from methanol (100 ml)thus obtaining the desired product (23.7 g; 0.0635 moles; yield 68%)with the following characteristics:

m.p. 72°-73° C.; [α]_(D) ²⁰ =-34.0° (c=1%, CHCl₃)

I.R. (Nujol): 1770, 1740 cm⁻¹ (stretching C=O)

¹ H-NMR (CDCl₃, TMS) (200M Hz).

These data are identical to those of the compound2-ethyl-2-(6-methoxy-2-naphthyl)-1.3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester, described in ex. 1.

EXAMPLE 25 Preparation of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(S),5(S)-dicarboxylic acid dimethyl ester

By processing as described in ex. 19 the2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(S), 5(S)-dicarboxylicacid dimethyl ester (9.35 g; 0.025 moles) the desired mixture ofdiastereoisomers is obtained (identified as 3' and 4') in 93% yield. Theratio between the diastereoisomers as determined by HPLC is 3':4'=93:7.The diastereoisomer 3', that is the prevailing one is the enantiomer ofthe diastereoisomer 3 described in ex. 6.

¹ H-NMR (CDCl₃ -TMS) (200 MHz)

Diastereoisomer 3' (SSR):the data are identical to those of thediastereoisomer 3 described in ex. 6.

Diastereoisomer 4' (SSS): the data are identical to those of thediastereoisiomer 4 described in ex. 6.

HPLC analysis performed as described in ex. 6.

Diastereoisomer 3': retention time 18.41 min.

Diastereoisomer 4': retention time 19.33 min.

EXAMPLE 26 Preparation of2(S)-hydroxy-3(S)-[2-(5-bromo-6-methoxy-2-naphthyl)propanoyl]-butanedioicacid dimethyl ester

By processing as described in ex. 17, a diastereoisomeric mixture of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(S),5(S)-dicarboxylic acid dimethyl ester (compounds 3' and 4' of ex. 25 inratio 3':4'=93.7; 2.66 g; 5.0 mmoles) a mixture of the desireddiastereoisomers is obtained (1.98 g; 4.2 mmoles; yield 84.4%)identified as compounds C' and D').

The ratio determined by ¹ H-NMR (200 MHz) is C': D'=85:15

¹ H-NMR (CDCl₃ -TMS) (200 MHz)

Diastereoisomer C' (SSR): the data are identical to those ofdiastereoisomer C described in ex. 9.

Diastereoisomer D' (SSS): the data are identical to those ofdiastereoisomer D described in ex. 9.

EXAMPLE 27 Preparation ofR(-)-2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid

A mixture of diastereoisomers C' and D' prepared according to ex. 26(ratio C': D'=85:15, 1.2 g; 2.56 mmoles), dimethoxyethane (18 ml), 12NHCl (18 ml) is kept at 88° C. under stirring for 1 h. The reactionmixture is cooled to room temperature and is then worked up as describedin ex. 10 (b). The so obtained crude acid is eluted through a silica gelcolumn (eluent hexane: diethylether 1:1). The2-(5-bromo-6-methoxy-2-naphthyl)propionic acid is obtained.M.p.=146°-148° C.; [α]₅₇₈ ²⁰ =-33.9° (c=0.5%; CHCl₃). This acid isesterified with diazomethane and the obtained methylester analyzed by ¹H-NMR (200 MHz) using an optically active shift agent (europium(III)-tris[3-(eptafluoropropylhydroxymethylene)-d-camphorate] in CDCl₃.The ratio between the enantiomers is R(-):S(+)=85:15. The methylesterwhen crystallized from methanol and hydrolized with an acid, leads tothe R(-)- 2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid in opticallypure form.

EXAMPLE 28 Preparation of2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylicacid dimethyl ester

1-(6-methoxy-2-naphthyl)-propan-1-one (465 g; 2.17 moles), dimethylesterof L(+) tartaric acid (773 g; 4.34 moles) and trimethyl orthoformate(461 g; 4.34 moles) are gradually heated up to complete solution. Thesolution is added with methanesulphonic acid (15 g; 0.155 moles). Thereaction mixture is kept at 100° C. for 4 hours, distilling off thevolatile compounds (about 400 g). It is cooled to 50° C. and pouredslowly under stirring into a 10% aqueous solution of NaHCO₃ (5 l). It isextracted with CH₂ Cl₂ and the organic extract is washed with water anddried on Na₂ SO₄. By evaporating the solvent under reduced pressure, aresidue containing the desired product as determined by HPLC analysis(743 g; yield 91.6%). is obtained. An analitycally pure product isobtained by crystallizing from 1.3 l of methanol (672 g; 1.8 moles;yield 82.8 %).

EXAMPLE 29 Preparation of the2-ethyl-2-[4-(2-methylpropyl)-phenyl]-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethylester

A mixture of 1-[4-(2-methylpropyl)-phenyl]-propan-1-one (110 g; 0.58moles), dimethyl ester of L(+) tartaric acid (206 g; 1.16 moles) andtrimethyl orthoformate (122.7 g; 1.16 moles) is gradually heated up tocomplete solution (50° C.). The solution is added with methanesulphonicacid (3.9 g; 0.04 moles). The reaction mixture is heated to 85° C. andkept at this temperature for 2 h, then cooled to room temperature andworked up as described in ex. 1. The crude product (210 g) is elutedthrough a silica gel column (eluent hexane:diethylether=8:2) and thedesired product is obtained (175.2 g; 0.501 moles; yield 86.5%) havingthe following characteristics:

I.R. (Neat): 1730-1760 cm⁻¹ (stretching C=O)

¹ H-NMR (CDCl₃ -TMS) (200 MHz) delta (ppm): 0.84 (d, 6H, J=6.4 Hz); 0.89(t, 3H, J=7.5 Hz); 1.8 (t-ept, 1H, J_(CH-CH).sbsb.3 -6.4 Hz,J_(CH-CH).sbsb.2 =7.1 Hz); 1.97 (q, 2H, J=7.5 Hz); 2.41 (d, 2H, J=7.1Hz); 3.78 (s, 3H); 3.84 (s, 3H); 4.78 (AB, 2H, J=5.7 Hz); 7-7.4 (AA'BB',4H, aromatic protons).

EXAMPLE 30 Preparation of diastereoisomers of the compound2-(1-bromoethyl)-2-[4-(2-methylpropyl)-phenyl]-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester

To a solution in 1,2-dichloroethane (70 ml) of2-ethyl-2-[4-(2-methylpropyl)phenyl]-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethylester (7.0 g; 20 mmoles obtainedaccording to ex. 29), deoxygenated and added with hydrobromic acid(0.324 g; 4 mmoles), it is added dropwise in 1 h under inert atmosphereat +15° C., a solution of bromine (3.20 g; 20 mmoles) in1,2-dichloroethane (7.0 ml) previously deoxygenated. The mixture is keptat 15° C. for an additional hour and then worked up as described inexample 6. The so obtained residue is eluted through a silica gel column(eluent hexane: diethylether 8:2) to give a mixture of the desireddiastereoisomers, identified as 11 and 12, in 77% yield.

The ratio between the compound 11 and 12 as determined by HPLC is 88:12¹ H-NMR (CDCl₃ -TMS) (200 MHz):

Diastereisomer 11 (RRS): delta (ppm): 0.87 (d, 6H, J=6.4 Hz); 1.61 (d,3H, J=7.1 Hz); 1.84 (t-ept, 1H, J_(CH-CH).sbsb.3 =6.4 Hz,J_(CH-CH).sbsb.2 =7.1 Hz); 2.45 (d, 2H, J=7.1 Hz); 3.53 (s, 3H); 3.84(s, 3H); 4.38 (q, 1H, J=7.1 Hz) 4.9 (AB, 2H, J=5.9 Hz); 7-7.4 (AA'BB',4H, aromatic protons).

Diastereoisomer 12 (RRR): delta (ppm): 0.87 (d, 6H, J=6.4 Hz); 1.58 (d,3H, J=7.1 Hz); 1.87 (t-ept, 1H, J_(CH-CH).sbsb.3 =6.4 Hz,J_(CH-CH).sbsb.2 =7.1 Hz); 2.53 (d, 2H, J=7.1 Hz); 3.6 (s, 3H); 3.83 (s,3H); 4.41 (q, 1H, J=7.1 Hz); 4.85 (AB, 2H, J=6.5 Hz); 7-7.4 (AA'BB', 4H,aromatic protons).

The HPLC analysis has been performed under the following conditions:Hewlett Packard instrument mod. 1090 with a variable wavelength UVdetector (mod. 1040 DAD).

Analytical conditions:

column BROWNLEE LABS RPS (5μ) spheri, 250 mm ×4.6 mm (internal diameter)

solvent A: bidistilled water

solvent B: acetonitrile:methanol=40:60

flow 2 ml/min.

percentage solvent B: 54%

column temperature: 50° C.

wavelength (λ): 222 nanometers

injection: 4 μl of a solution containing 0.5 mg/ml of product inacetonitrile:methanol 40:60

retention times:

diast. 11=22.61 min.

diast. 12=23.63 min.

EXAMPLE 31 Preparation of2(R)-hydroxy-3(R)-(2-[4-(2-methylpropyl)-phenyl]-propanoyl-butanedioicacid dimethyl ester

Operating under analogous conditions to those described in Example 17,after work up of the reaction mixture, starting from a mixture ofdiastereoisomers 11 and 12 (3.0 g; 7.0 mmoles) (ratio determined byHPLC, 11:12=88:12), with a reaction time of 6 hours at +28° C. themixture of diastereoisomeric esters indicated herein as I and J isobtained.

¹ H-NMR (CDCl₃ -TMS) (200 MHz)

Diastereoisomer I (RRS): delta (ppm): 0.87 (d, 6H, J=6.4 Hz); 1.485 (d,3H, J=7.1 Hz); 1.8 (t-hept, 1H, J_(CH-CH).sbsb.3 =6.4 Hz,J_(CH-CH).sbsb.2 =7.1 Hz); 2.42 (d, 2H, (d, 2H, J=7.1 Hz); 3.15 (d, 1H,J=7.05 Hz); 3.32 (s, 3H); 3.78 (s, 3H); 38 (q, 1H, J=7.1 Hz); 4.67 (dd,1H, J_(CH-CH) =2.3 Hz, J_(CH-OH) =7.05 Hz); 5.36 (d, 1H, J=2.3 Hz);7.02-7.16 (AA'BB', 4H, aromatic protons).

Diastereoisomer J (RRR): delta (ppm): 0.87 (d, 6H, J=6.4 Hz); 1.525 (d,3H, J=7.1 Hz); 1.825 (t-hept, 1H, J_(CH-CH).sbsb.3 =6.4 Hz,J_(CH-CH).sbsb.2 =7.1 Hz); 2.43 (d, 2H, J=7.1 Hz); 3.15 (d, 1H, J=7.05Hz); 3.62 (s, 3H); 3.69 (s, 3H); 3.82 (q, 1H, J=7.1 Hz); 4.73 (dd, 1H,J_(CH-CH) =2.3 Hz, J_(CH-OH) =7.05 Hz); 5.43 (d, 1H, J=2.3 Hz); 7.04-7.2(AA'BB', 4H, aromatic protons).

EXAMPLE 32 Preparation of 2-[4-)2-methylpropyl)-phenyl]-propionic acid(Ibuprofen)

Operating in a analogous manner to that described in Example 10(b),crude 2-[4-(2-methylpropyl)-phenyl]-propionic acid is obtained from amixture of diastereoisomeric esters I and J, prepared as described inExample 31 (1.37 g; 3.74 mmoles). After chromatography a silica gel, thepure acid is obtained (0.7 g). [α]_(D) ²⁰ =+19° (C=1%, 95% ethanol).

EXAMPLE 33 Preparation of2-(1-bromoethyl)-2-[4-(2-methylpropyl)-phenyl]-1,3-dioxolane-4(R),5(R)-dicarboxylic acid

A solution of diastereoisomers 11 and 12 (see Example 30)(10.0 g; 0.0233moles) in methylene chloride (20 ml) is added dropwise to a solution ofsodium hydroxide (1.87 g; 0.0466 moles) in water 25 ml) and methanol(100 ml), kept under stirring at 20° C. The reaction mixture is keptunder stirring at this temperature for 1 hour. The solvent is evaporatedunder reduced pressure. The residue is taken up in water (100 ml) andacidified to pH 1, with concentrated HCl. It is extracted withdiethylether (3×50 ml). The organic phase is extracted with a 10% sodiumbicarbonate solution (3×50 ml). The alkaline solution is acidified topH₁, with concentrated HCl and extracted with diethylether (3×50 ml).The combined organic phases are dried over sodium sulphate, and thesolvent is evaporated under reduced pressure to give the crude product(8.3 g; acidimetric assay 92%; yield 81%). HPLC analysis of a sampleesterified with diazomethane shows that the ratio of the twodiastereosiomers 13 and 14 is 87:13.

¹ H-NMR (CDCl₃ -TMS) delta (ppm)

Diastereoisomer 13 (RRS): delta (ppm): 0.87 (d, 6H, J=6.4 Hz); 1.59 (d,3H, J=7.1 Hz); 1.95 (t- ept, 1H, J_(CH-CH).sbsb.3 =6.4 Hz,J_(CH-CH).sbsb.2 =7 Hz); 2.55 (d, 2H, J=7 Hz); 4.42 (q, 1H, J=7.1 Hz);4.88 (AB, 2H, J=6.4 Hz); 7-7.4 (AA'BB', 4H, aromatic protons); 8.2 (s,2H). Diastereoisomer 14 (RRR): delta (ppm)0 0.87 (d, 6H, J=6.4 Hz); 1.58(d, 3H, J=7.1 Hz); 1.95 (t- ept, 1H, J_(CH-CH).sbsb.3 =6.4 Hz,J_(CH-CH).sbsb.2 =7 Hz); 2.55 (d, 2H, j=7 Hz); 4.42 (q, 1H, J=7.1 Hz);4.8 (AB, 2H, J=6.4 Hz); 7-7.44 (AA'BB', 4H, aromatic protons); 8.2 (s,2H).

EXAMPLE 34 Preparation of(+)-2(R)-hydroxy-3(R)-[2(S)(6-methoxy-2-naphthyl)propanoyl]-butanedioicacid dimethyl ester

A solution of triethylamine (4.45 g; 0.044 moles) in methylene chloride(10 ml) is added dropwise in a period of 5 minutes to a mixture of2(R),3(R)-dihydroxy-butanedioic acid dimethyl ester (L(+)tartaric aciddimethyl ester)(44.5 g; 0.25 moles) and methylene chloride (90 ml),cooled to -10° C. and kept under stirring, followed by the dropwiseaddition in a period of 20 minutes of a solution, in methylene chloride(25 ml), of S(+)2-(6-methoxy-2-naphthyl)-propionyl chloride (5.0 g:0.020 moles) prepared as described in Japanese patent application No.57/145841 (C.A. 98, 72492h). The reaction mixture is then poured into a10% sodium bicarbonate solution (200 ml), extracted with methylenechloride (100 ml), and the organic phase washed with dilute hydrochloricacid and dried over sodium sulphate. The residue (5.5 g) is obtained byevaporating the solvent under reduced pressure, and is crystallised froma mixture of heptane and diethylether (1:1, 165 ml). The desired product(diastereoisomerr A, see Example 3) (2.75 g) is obtained, having thefollowing characteristics:

I.R. (C=5% in CHCl₃) 1750 cm⁻¹

[α]_(D) ²⁰ =+73.7° (C=1%, CHCl₃)

M.P.=77°-79° C.

¹ H-NMR (CDCl₃ -TMS) (200 MHz): delta (ppm): 1.58 (d, 3H, J=7.4 Hz);3.07 (s, 3H); 3.31 (d, 1H, J=7.4 Hz); 3.79 (s, 3H); 3.87 (s, 3H); 3.96(q, 1H, J=7.4 Hz); 4.66 (dd, 1H, J_(CH-CH) =2.3 Hz, J_(CH-OH) =7.4 Hz);5.37 (d, 1H, J=2.3 Hz); 7-7.8 (6H, aromatic system). A solution ofbromine (0.410 g; 2.56 mmoles) in 1,2-dichloroethane (3 ml) is added in15 minutes to a solution of the ester thus obtained in1,2-dichloroethane (10 ml), cooled to 0° C. The reaction mixture is keptat 0° C. for 1 hour, and is then poured into a 10% sodium bicarbonatesolution (10 ml) and extracted with methylene chloride (10 ml). Thecombined organic phases are washed with water (20 ml×2), dried oversodium sulphate, and the solvent evaporated under referred pressure.

The residue (1.14 g) is crystallized from methanol.(+)-2(R)-hydroxy-3(R)-[2-(S)-(5-bromo-6-methoxy-2-naphthyl)-propanoyl)]-butanedioicacid dimethyl ester is obtained (0.889 g; 1.9 mmoles; yield 74%); M.P.124°-126° C.; [α]_(D) ²⁰ =+61.4° (C=1%; CHCl₃). The chemical-physicaldata (M.P., [α]_(D) ²⁰ and ¹ H-NMR-200 MHz) are equal to those of thediastereoisomer ester C described in Example 9. When treated withpalladium-on-carbon and hydrogen at atmospheric pressure and roomtemperature in the presence of triethylamine, the product produces thediastereoisomer A.

EXAMPLE 35 Preparation of the mixture of diastereoisomers 7 and 8 of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid

A solution of bromine (171 g; 1.68 moles) in carbon tetrachloride (360ml) is added dropwise in 1 hour to a solution of2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester (200 g; 0.534 moles) in carbon tetrachloride (2000ml) kept under an inert atmosphere at 0° C.

The reaction mixture is kept at 0° C. for 2 hours, and worked asdescribed in Example 6.

The crude product thus obtained (351 g) is dissolved in methanol (2000ml), and a solution of sodium hydroxide (38.4 g; 0.96 moles) in water(384 ml) is added dropwise to the resultant solution at ambienttemperature in 1 hour. The reaction mixture is kept at ambienttemperature under stirring for 20 hours. The methanol is evaporatedunder vacuum, maintaining the initial volume of the solution by addingwater.

The pH of the aqueous solution obtained is adjusted to 7 with dilutehydrochloric acid. The solution is then extracted with methylenechloride and the aqueous solution is acidified with concentrated HCl topH 1.

It is extracted with diethylether(3×250 ml) and the combined organicphases are washed with water and dried over sodium sulphate. The solventis evaporated under vacuum to give a residue that is crystallised frommethylene chloride.

A mixture of the two diastereoisomers 7 and 8 of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid is obtained (205 g; 0.407 moles; yield 76%) in the ratio of7:8=94:6.

EXAMPLE 36

A mixture of the two diastereoisomers 3 and 4 of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester in the ratio 3:4=9:1 (1 g; 1.87mmoles), zinc bromide (0.84 g; 3.75 mmoles) and 1,2-dichloroethane (12ml) is heated at reflux (83° C.), under stirring and under nitrogen, for66 hours.

The reaction mixture is cooled to ambient temperature, and water (5 ml)is added. The phase are separated and the organic phase is dried oversodium sulphate.

The solvent is evaporated under vacuum to give a residue (0.9 g) towhich dioxane (10 ml) and concentrated HCl (5 ml) are added. The mixtureis heated to 70° C. under, stirring, for 2 hours, is then diluted withwater (10 ml) and extracted with diethylether (3×20 ml). The combinedorganic extracts are washed with water and dried over sodium sulphate.Evaporation of the solvent under vacuum gives a residue which bychromatography on silica gel (eluent hexane:ethyl ether=7:3) gives2-(5-bromo-6-methoxy-2-naphthy)-propionic acid (0.28 g; 0.9 mmoles;yield 48%);

M.P. 166°-167° C.

[α]_(D) ²⁰ =+15.44° (C=0.5, CHCl₃).

The ratio of the enantiomeric acids S(+)/R(-) is 65:35.

EXAMPLE 37 Preparation of 2-(S)-(5-bromo-6-methoxy-2-naphthyl)-propionicacid methyl ester from2-(1-(S)-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester

A mixture of pure2-(1-(S)-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid diemthyl ester (1.03 g, 1.93 mmol), silvertrifluoromethanesulfonate (0.6 g, 2.31 mmol) and methanol (5 ml) isheated at reflux for 7 hours. The reaction mixture is cooled at roomtemperature, filtered, poured into water, and extracted withdichloromethane. The combined organic extracts are washed with water,dried (Na₂ SO₄), and filtered.

Evaporation of the solvent under reduced pressure gives the opticallypure 2-(S)-(5-bromio-6-methoxy-2-naphthyl)-propionic acid methyl ester.

M.P. 94°-95° C.

[α]_(D) ²⁰ =+52° (c=0.5, CHCl₃)

The product is found to be optically pure by ¹ H-NMR (200 MHz) analysys,carried out in CDCl₃ using an optically active shifting agent (Europium(III) Tris-[3-(eptafluoropropylhydroxymethylene)-d-camphorate]

EXAMPLE 38 Bromination of2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid

Bromine (0.32 g; 2 mmol) is added dropwise, in 5 minutes at 15° C. andunder argon, to a suspension of2-ethyl-2-(6-methoxy-2-nahthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid (0.346 g, 1 mmol). The reaction mixture is heated at 40° C. andkept at 40° C. for 12 hours; then it is poured into a 10% aqueoussolution of sodium bicarbonate and extracted with diethylether. Theaqueous phase is acidified to pH=1 with conc. HCl and extracted withdiethylether. The combined organic extracts are washed with water, dried(Na₂ SO₄), and filtered. Evaporation of the solvent under reducedpressure gives a reaction crude which, after purification leads to adiastereoisomeric mixture of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid in ratio 7:8=81:19 (determined by ¹ H-NMR).

¹ H-HMR (90 MHz, Acetone-d₆ -TMS) δ (ppm):

Diastereoisomer 7 (RRS): 1.70 (3H, d, J=6.8 Hz); 4.03 (3H, s); 4.66 (1H,q, J=6.8 Hz); 4.95 (2H, ABq, Δν=15.31, J=6.9 Hz); 7.45-8.18 (5H, m).

Diastereoisomer 8 (RRR): 1.70 (3H, d, J=6.8 Hz); 4.03 (3H, s); 4.66 (1H,q, J=6.8 Hz); 4.95 (2H, ABq, Δν=14.46, J=6.6 Hz); 7.45-8.18 (5H, m). Thediastereoisomeric ratio is confirmed analyzing by ¹ H-NMR and HPLC theproduct obtained by esterification with diazomethane.

EXAMPLE 39 Preparation of the diastereoisomeric mixture of2-(1-iodoethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester

A solution of2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester (0.935 g, 2.5 mmol) and of iodine monochloride (0.81g, 5 mmol) in dichloromethane (5 ml) is kept under nitrogen and at 15°C. for 24 hours. The reaction mixture is poured into a 10% aqueoussolution of sodium bicarbonate, and extracted with additionaldichloromethane. The combined organic extracts are washed with a 25%aqueous solution of sodium thiosulphate, with water, dried (Na₂ SO₄),filtered, and concentrated in vacuo. Purification of the residue bycolumn chromatography (silical gel, eluent hexane:diethyl ether=7:3)gives the diastereoisomeric mixture of2-(1-iodoethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester 15 and 16 in ratio 15:16=60:40 (determined by ¹H-NMR).

¹ H:NMR (200 MHz, CDCl₃ -TMS) δ (ppm):

Diastereoisomer 15 (RRS) 1.80 (3H, d, J=7 Hz); 3.44 (3H, s); 3.84 (3H,s); 3.90 (3H, s); 4.58 (1H, q, J=7 Hz); 4.95 (2H, ABq, Δν=20.70, J=6Hz); 7.8-8.0 (6H, m).

Diastereoisomer 16 (RRR) 1.80 (3H, d, J=7 Hz); 3.58 (3H, s); 3.84 (3H,s); 3.90 (3H, s); 4.58 (1H, q, J=7 Hz); 4.87 (2H, ABq, Δν=46.04, J=6.8Hz); 7.8-8.0 (6H, m).

EXAMPLE 40 Preparation of 2-(6-methoxy-2-naphthyl)-propionic acid from adiastereoisomeric mixture of2-(1-iodoethyl)-2-(6-methoxy-2-naphtyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid diemthyl ester

Silver trifluoromethanesulfonate (1.2 g, 4.8 mmol) is added, under argonand stirring, at 15° C. to solution of a diastereoisomeric mixture of2-(1-iodoethyl9-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester in ratio 60:40 (1.6 g, 3.2 mmol) in1,2-dichloroethane (20 ml). The reaction mixture is kept in the dark at15° C. for 3 hours; then it is filtered, poured into water. The organiclayer is separated, washed with water, dried (Na₂ SO₄), filtered andconcentrated in vacuo.

The residue is dissolved into dioxane (5 ml) and conc. HCl (5 ml) isadded. The mixture is heated at 70° C. for 2 hours cooled at roomtemperature, poured into water, and extracted with diethyl ether. Thecombined organic extracts are washed with water and back-extracted witha 2% aqueous solution of sodium bicarbonate. The aqueous phase isacidified with conc. HCl and extracted with diethyl ether. The combinedorganic extracts are washed with water, dried (Na₂ SO₄), filtered.Evaporation of the solvent under reduced pressure gives the2-(6-methoxy-2-naphthyl)-propionic acid.

M.p.=154°-155° C.

[α]_(D) ²⁰ =+6.02 (c=1, CHCl₃)

HPLC analysis, carried out as described in J. Pharm. Sci. 68, 112 (1979)and H-NMR (200 MHz) analysis carried out on the methyl ester in CDCl₃using an optically active shifting agent (Europium (III)Tris-[3(eptafluoropropylhydroxymethylen)-d-camphorate]) shows anenantiomeric ratio S(+):R(-)=55:45.

EXAMPLE 41 Preparation of2-ethyl-2-(6-hydroxy-2-naphtyl)-1,3+dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester

A mixture of 1-(6-hydroxy-2-naphthyl)-propan-1-one (25 g, 0.125 mol),2(R), 3(R)-dihydroxybutanedioic acid dimethyl ester (178 g, 1 mol),trimethyl orthoformate (54 g, 0.51 mol), and of methanesulphonic acid(0.84 g, 0.088 mol) is heated, under argon and under stirring, at 70° C.for 4 hours.

The reaction mixture is cooled at room temperature, poured into a 10%aqueous solution of sodium carbonate (400 ml), and extracted withdiethylether (4×50 ml). the combined organic extracts are washed withwater (3×150 ml), dried (Na₂ SO₄), filtered, and concentrated in vacuo.

Purification of the crude by column chromatography (silica gel, eluenthexane:diethylether=1:1) gives the pure2-ethyl-2-(6-hydroxy-2-naphtyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethylester (17 g) as an oil.

¹ H-NMR (90 MHz, CDCl₃ -TMS) δ(ppm): 1.93 (3H, t, J=6.5 Hz); 2.10 (2H,q, J=6.5 Hz); 3.43 (3H, s); 3.80 (3H, s); 4.83 (2H, SABq, Δν=6.7, J=6Hz); 6.00 (1h, s, OH); 7.07-7.85 (6H, m).

EXAMPLE 42 Preparation of the diastereoisomeric mixture of2-(1-bromoethyl)-2-(5-bromo-6-hydroxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester

A solution of bromine (5.12 g, 32 mmol) in carbon tetrachloride (5 ml)is added dropwise in 10 minutes, under argon and at 15° C., to asolution of2-ethyl-2-(6-hydroxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester (6 g, 16 mmol) in carbon tetrachloride (60 ml). Thereaction mixture is kept at 15° C. for 2 hours and poured into a 5%aqueous solution of sodium thiosulfate (200 ml).

The organic layer is separated, washed with water, dried (Na₂ SO₄),filtered, and concentrated in vacuo.

Purification of the reaction crude by column chromatography (silica gel,hexane:diethyl ether=1:1) gives a diastereoisomeric mixture of2-(1-bromoethyl)-2-(5-bromio-6-hydroxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester (8 g, 15 mmol; yield 93%) as a solid.

Ratio diastereoisomers 17:18=90:10 (determined by ¹ H-NMR and HPLC).

m.p. 116°-117° C.

¹ H-NMR(200 MHz, CDCl₃ TMS) δ (ppm):

diastereoisomer 17 (RRS) 1.66 (3H, d, J=7 Hz); 3.52 (3H, s); 3.88 (3H,s); 4.48 (1H, q, J=7 Hz): 4.96 (2H, ABq, Δν=27.80, J=6.1 Hz); 7.2-8.0(5H, m).

diastereoisomer 18 (RRR). 1.62 (3H, d, J=7 Hz); 3.56 (3H, s); 3.87 (3H,s); 4.48 (1H, q, J;32 7 Hz); 4.90 (2H, ABq, Δν=35.44, J=6.3 Hz); 7.2-8.0(5H, m).

The diastereoisomeric ratio 17(RRS):18(RRR)=90:10 is confirmed byconverting the product in the diastereoisomeric mixture of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester 3 and 4 followingthe present procedure:

a mixture of the product (0.52 g, 1 mmol), potassium carbonate (1.38 g,10 mmol), methyl iodide (0.426 g, 3 mmol), and of acetone (10 ml) iskept under stirring at room temperature for 4 hours.

The reaction mixture is filtered and concentrated in vacuo. The residue,so obtained, is a diastereoisomeric mixture of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester in ratio 3(RRS):4(RRR)=90:10 (determined by ¹ H-NMRand HPLC).

EXAMPLE 43 Preparation of 2-(5-bromo-6-hydroxy-2-naphthyl)-propionicacid

A mixture of the diastereoisomers 17 and 18 in the ratio 90:10 (seeExample 42) (0.57 g; 11 moles), sodium hydroxide (0.132 g; 33 mmoles)and water (20 ml) is heated to 60° C. for 2 hours. The reaction mixtureis cooled to room temperature, acidified to pH 1 with concentrated HCland extracted with diethylether.

The combined organic phases are washed with water, dried over sodiumsulphate and concentrated under vacuum. The residue thus obtained ispurified by chromatography on silica gel, to give pure2-(5-bromo-6-hydroxy-2-naphthyl)-propionic acid.

On the basis of ¹ H-NMR analysis as described in Example 4, the ratio ofthe S to R enantiomer is 90:10.

EXAMPLE 44 Preparation of2-(1-bromoethyl)-2-(5-bromo-6-hydroxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid

A mixture of the diastereoisomers 17 and 18 in the ratio 90:10 (seeExample 42) (5.6 g; 0.0108 moles), water (52 ml), methanol (30 ml) andan aqueous 10% (w/v) sodium hydroxyde solution (11.5 ml) is kept understirring at room temperature for 6 hours.

The reaction mixture is then acidified with concentrated HCl to pH 1 andextracted with diethylether. The combined organic extracts are washedwith water and dried over sodium sulphate.

Evaporation of the solvent under vacuum gives the diastereoisomers 19and 20 (4.8 g; 0.0098 moles; yield 90%) in the ratio 19:20=92:8

¹ H-NMR (90 MHz, CDCl₃ -TMS) δ (ppm)

diastereoisomer 19 (RRS): 1.66 (d, 3H, J=7 Hz); 4.63 (q, 1H, J=7 Hz);4.93 (2H, ABq, Δν=16.42, J=6.5 Hz); 7.23-8.15 (m, 5H); 8.27 (1H, broad)

EXAMPLE 45 Preparation of 2-(5-bromo-6-hydroxy-2-naphthyl)-propionicacid

A mixture of the diastereoisomers2-(1-bromoethyl)-2-(5-bromo-6-hydroxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid 19 and 20 (1.76 g; 3.6 mmoles) in the ratio 19:20=92.8 (see Example44), sodium bicarbonate (2.4 g; 28 mmoles) and water (50 ml) is heatedunder reflux, under stirring, for 4 hours. The reaction mixture, cooledto ambient temperature, is acidified to pH 1 with 6N HCl and extractedwith diethylether. The combined organic phases are washed with water anddried over sodium sulphate. Evaporating the solvent under vacuum gives acrude product to which dimethoxyethane (17 ml) and 12N HCl (17 ml) areadded. The reaction mixture is heated under reflux, under stirrinng for2 hours, cooled and extracted with diethylether. The combined organicphases are washed with water and dried over sodium sulphate. Evaporationof the solvent under vacuum gives a residue which is chromatographedover silica gel (eluent diethyletherhexane 7:3). In this manner the pureacid is obtained [α]_(D) ²⁰ =+42.3 (C=1 in acetone). A samples isesterified with diazomethane. The methyl ester is analysed by ¹ H-NMR(200 MHz) using an optically active shift agent. The ratio of theenantiomeric acids (+)S/(-)R is 98:2.

EXAMPLE 46

A solution of silver tetrafluoroborate (0.6 g; 3.08 mmoles) in1,2-dichloroethane (4 ml) is added dropwise to a mixture of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester (diastereoisomer 3:diastereoisomer 4=94.6, ratiodetermined by HPLC) (1.33 g; 2.5 mmoles) and 1,2-dichloroethane (10 ml)kept under stirring at +15° C. After 73 hours the reaction mixture ispoured into water (20 ml) and filtered through celite, the filtratebeing washed with methylene chloride (10 ml).

The organic phase is washed with water (2×20 ml) and dried over sodiumsulphate.

Evaporation of the solvent under reduced pressure gives a residue (0.95g) in which the diastereoisomers C and D of the ester are present in theratio C:D=79.21, determined by ¹ H-NMR analysis at 60 MHz.

In an analogous test carried out in parallel, in which water (0.1 g; 6mmoles) was added to the reaction mixture before adding the sodiumtetrafluoroborate, the ratio of the diastereoisomers, after 73 hours, isC:D=94.6.

EXAMPLE 47 Preparation of 1-(4-chlorophenyl)-3-methyl-butan-1-one

3-methyl-butyrryl chloride (128.6 g; 1.07 moles) is added in 15 minutesto a suspension of aluminum chloride (153.8 g; 1.15 moles) in methylenechloride (200 ml) cooled to -5° C. and kept under stirring in an inertatmosphere.

At the end of the addition, the mixture is heated to +° C. andchlorobenzene (100 g; 0.89 moles) is added in 15 minutes. The reactionmixture is heated to +45° C. for 7 hours, then cooled to ambientetemperature and poured under stirring into concentrated HCl (200 ml) andice (1500 g).

The aqueous phase is extracted with methylene chloride (3×300 ml). Theorganic extracts are washed with a 1% sodium hydroxide solution (3×700ml) and with water (3×700 ml).

After drying over sodium sulphate, the organic solvent is evaporatedunder reduced pressure to give a residue (161 g) which, aftercrystallization from n-hexane (100 ml) provides1-(4-chlorophenyl)-3-methylbutan-1-one (121.5 g; 0.62 moles; yield69.4%).

M.P.=39°-40°

I.R. (Nujol)=1680-1700 cm⁻¹ (stretching c=0)

¹ H-NMR (CDCl₃ -TMS) (90 MHz): δ (ppm): 0.97 (d, 6H, J=6,7 Hz); 2.27 (m,1H, J_(CH-CH).sbsb.3 =6.7 Hz); 2.77 (part AB of and ABX system, 2H);7.3-7.9 (AA'BB', 4H aromatic protons)

EXAMPLE 48 Preparation of2-(4-chlorophenyl)-2-(2-methylpropyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester

A mixture of 1-(4-chlorophenyl)-3-methyl-butan-1-one (40.0 g; 0.204moles), 2(R),3(R)-dihydroxy-butanedioic acid dimethyl ester (72.4 g;0.407 moles) and trimethyl orthoformate (43.1 g; 0.406 moles) is heatedgradually untill a complete solution (60° C.). Methanesulphonic acid(1.4 g; 0.015 moles) is added to the solution, which is then heated to75° C.

After a reaction time of 3 hours, the mixture is cooled to ambienttemperature and poured into a 10% sodium bicarbonate solution (250 ml)under vigorous stirring. The aqueous phase is extracted with methylenechloride (2×250 ml) and the organic extracts washed with water (2×400ml). After drying the organic phase over sodium sulphase, the solvent isevaporated under reduced pressure.

The residue obtained (68.7 g) is chromatographed over silica gel (eluenthexane:diethylether=8:2).

2-(4-chlorophenyl)-2-(2-methylpropyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester (41 g; 0.115 moles; yield 56,4%) is obtained.

M.P.=40° C.

[α]_(D) ²⁰ =+21.6° (c=1%; CHCl₃)

I.R. (Nujol)=1770-1740 cm⁻¹ (stretching c=0)

¹ H-NMR (200 MHz) (CDCl₃ -TMS): δ (ppm): 0.87 (d, 6H, J=6.9 Hz); 1.67(m, 1H, J_(CH-CH).sbsb.3 =6.9 Hz); 1.86 (part AB of an ABX system, 2H);3.55 (s, 3H); 3.82 (s, 3H); 4.74 (ABq, 2H, J=6.0 ;l Hz); 7.2-7.4(AA'BB', 4H aromatic protons).

EXAMPLE 49 Preparation of2-(1-bromo-2-methylpropyl)-2-(4-chlorophenyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester

A solution of bromine (8.05 g; 0.05 moles) in 1,2-dichloroethane (18 ml)is added in 1 hour and ;b 15 minutes to a solution of2-(4-chlorophenyl)-2-(2-methylpropyl9-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester (18.0 g; 0.05 moles) in 1,2-dichloroethane (180 ml),to which methanesulphonic acid (3.6 g; 0.038 moles) had been previouslyadded, the reaction mixture being kept under stirring in an inertatmosphere at +15° C. After 1 hours at 15° C., the mixture is pouredinto a 10% sodium carbonate solution (400 ml) under vigorous stirring.and extracted with methylene chloride (2×250 ml).

The organic phase is washed with water (2×400 ml) and dried over sodiumsulphate.

After evaporating the solvent under reduced pressure, a residue (20.5 g)is obtained which contains the two diastereoisomers of the2-(1-bromo-2-methylpropyl)-2-(4-chlorophenyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester, here indicated as 21 and 22, in the ratio 21:22;3297.3 (ratio determined by ¹ H-NMR (300 MHz) analysis and confirmed byHPLC analysis). By crystallization from n-hexane (60 ml), thediastereoisomer 21 is obtained (13.6 g; ;b 0.031 moles; yield 62.5%),and is found to be pure on

¹ H-NMR analysis (300 MHz).

¹ H-NMR (300 MHz) (CDCl₃ -TMS)

Diastereoisomer 21 (RRS): 0.93 (d, 3H, J=6.9 Hz); 0.98 (d, 3H, J=6.6Hz); 1.70 (m, 1H, J_(CH-CH) =1.8 Hz, J_(CH-CH).sbsb.3 =6.6 Hz,J_(CH-CH).sbsb.3 =6.9 Hz); 3.59 (s, 3H); 3.85 (s, 3H), 4.28 (d, 1H,J=1.8 Hz); 4.87 (ABq, 2H, J=6.2 Hz); 7.3-7.5 (AA'BB', 4H aromaticprotons).

The HPLC analysis was performed under the following conditions: HewlettPackard instrument mod. 1090 with U.V. variable wavelength U.V. detector(mod. 1040 DAD).

Analytical conditions:

Brownlee column LABS RP 8 (5μ)balls; 250 ml×4.6 mm (inner diameter)

Solvent A: bidistilled water

Solvent B: methanol

Flor: 1.7 ml/min

Percentage solvent B: 63%

Column temperature: 40° C.

Wavelength (λ): 230 nanometer

Injection 5μ of a solution containing 0.5 mg/ml of product in methanol

Retention times:

Diastereoisomer 21=11.71 minutes

Diastereoisomer 22=12.85 minutes

EXAMPLE 50 Preparation of2(R)-hydroxy-3(R)-[2(S)-(4-chlorophenyl)-3-methylbutanoyl]-butanedioicacid dimethyl ester

A solution of silver tetrafluoroborate (1.6 g, 8.2 mmol) in1,2-dichloroethane (15 ml) was aded in 20 minutes to a mixture of2-(1-bromo-2-methylpropyl)-2-(4-chlorophenyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester (diastereoisomer 21) (3 g, 6.9 mmol), water (0.2 g)and of 1,2-dichloroethane (18 ml) at 20° C. The reaction mixture washeated at 50° C. for 7 hours, cooled at 20° C. and poured in water (50ml). The mixture was filtered on celite and the precipitate washed withdichloromethane (30 ml).

The organic phase was separeted, washed with water, dried over sodiumsulfate, and concentrated in vacuo. Purification of the reaction crude(2.3 g) by column chromatography (silica gel; eluenthexane:diethyleter=1:1) gave the pure diastereoisomer2(R)-hydroxy-3(R)-[2-(S)-(4-chlorophenyl)-3-methylbutanoyl]-butanedioicacid dimethyl ester K (1.95 g, 5.2 mmol; yield 75.9%).

¹ H-NMR (300 MHz, CDCL₃ -TMS) delta (ppm): 0.68 (d, 3H, J_(CH-CH).sbsb.3=6.9 Hz); 1.06(d, 3H, J=6.2 Hz); 2.33(m, 1H, J_(CH-CH) =10.6 Hz,J_(CH-CH).sbsb.3 =6.9 Hz, J_(CH-CH).sbsb.3 =6.2 Hz); 3.22(d, 1H,J_(CH-CH).sbsb.3 =6.95 Hz); 3.24(d, 1H, J=10.6 Hz); 3.30(s, 3H); 3.77(s,3H); 4.63(dd, 1H, J_(CH-CH) =2.6 Hz); 5.36(d, 1H, J_(CH-CH) =2.6 Hz);7.21-7.28(AA'BB', 4H, aromatic protons).

EXAMPLE 51 Preparation of2(R)-hydroxy-3(R)-[2(S)-(4-chlorophenyl)-3-methylbutanoyl]-butandioicacid

A mixture of2(R)-hydroxy-3(R)-[2(S)-(4-chlorophenyl)-3-methylbutanoyl]-butanedioicacid dimethyl ester (diastereoisomer K) (1 g, 2.6 mmol),1,2-dimethoxyethane (18.3 ml) and of conc HCl (18.3 ml) was heated,under stirring, at 70° C. for 1 hour. The reaction mixture was cooled atroom temperature, poured into water (50 ml) and extracted withdichloromethane (2×50 ml). The organic phase was extracted with a 10%aqueous solution of sodium bicarbonate (4×50 ml). The aqueous phase wasacidified with conc HCl to pH 1 and extracted with dichloromethane (3×50ml). The combined organic phase was washed with water, anhydrified oversodium sulfate, filtered, and concentrated in vacuo.

Crystallization of the residue (0.8 g) gave the pure2(R)-hydroxy-3(R)-[2(S)-(4-chlorophenyl)-3-methylbutanoyl]-butanedioicacid (0.4 g) (diastereisomer L).

M.p.=173°-175° C.

¹ H-NMR (300 MHz, CDCl₃ -TMS) delta (ppm): Diastereoisomer L (RRS)0.56(d, 3H, J=6.7 Hz); 0.94(d, 3H, J=6.5 Hz); 2.20(m, 1H,J_(CH-CH).sbsb.3 =6.7 Hz, J_(CH-CH).sbsb.3 =6.5 Hz, J_(CH-CH) =10.4 Hz);3.16(d, 1H, J=10.4 Hz); 4.65(d, 1H, J_(CH-CH) =2.1 Hz); 5.33(d, 1H,J=2.1 Hz); 7.00-7.27(AA'BB', 4H, aromatic protons).

¹ H-NMR analysis carried out on the corresponding dimethyl ester,obtained by reaction with diazomethane, showed only the presence thediastereoisomer K (RRS).

EXAMPLE 52 Preparation of (+)-2(S)-(4-chlorophenyl)-3-methylbutanoicacid

A mixture of the diastereisomer K (0.9 g, 2.3 mmol), 1,4-dioxane (16 ml)and of conc HCl (16 ml) was heated, under stirring, at 90° C. for 18hours. The reaction mixture was cooled at room temperature, diluted withwater (30 ml), and extracted with dichloromethane (3×20 ml). The organicphase was extracted with a 10% aqueous solution of sodium bicarbonate(5×10 ml). The aqueous phase was acidified with conc HCl to pH 1 andextracted with dichloromethane (5×10 ml). The combined organic phase waswashed with water, dried over sodium sulfate, and concentrated in vacuo.

Purification of the reaction crude (0.25 g) by column chromatography(silica gel; eluente hexane:diethylether=80:20) gave pure2(S)-(4-chlorophenyl)-3-methylbutanoic acid (0.2 g).

[α]_(D) ²⁰ =+38.6° (c=1%, chloroform)

EXAMPLE 53 Preparation of2-(1(S)-bromo-2-methylpropyl)-2-(4-chlorophenyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid

A solution of the diastereoisomer 21 (10 g, 23 mmol) in dichloromethane(10 ml) was added dropwise in 15 minutes at 20° C. to a solution ofsodium hydroxyde (2 g, 50.6 mmol) in water (25 ml) and methanol (100ml). The reaction mixture was kept at 20° C. for 1 hour and the solventremoved under reduced pressure. Water (100 ml) was added. The solution,so obtained, was acidified with one HCl to pH 1 and extracted withdiethylether (3×75 ml). The organic phase was extracted with a 10%aqueous solution of sodium bicarbonate (3×75 ml). The aqueous phase wasacidified with conc HCl to pH 1 and extracted with diethylether (3×75ml). The conbined organic extracts were washed with water andanhydrified over sodium sulfate. Evaporation of the solvent underreduced pressure gave the2-(1(S)-bromo-2-methylpropyl)-2-(4-chlorophenyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid (diastereoisomer 23) (7.2 g, 19.8 mmol; yield 66%).

¹ H-NMR (300 MHz, CDCl₃ -TMS) delta (ppm): diastereoisomer 23(RRS)0.92(d, 3H, J=6.6 Hz); 0.98(d, 3H, J=6.2 Hz); 1.58(m, 1H, J_(CH-CH) =1.8Hz, J_(CH-CH).sbsb.3 =6.6 Hz, J_(CH-CH).sbsb.3 =6.2 Hz); 4.37(d, 1H,J=1.8 Hz); 4.86(ABq, 2H, J=6.2 Hz); 7.36-7.46(AA',BB', 4H, aromaticprotons).

The presence of one diastereoisomer was confirmed by HPLC analysiscarried out on a sample of the corresponding dimethyl ester(diastereoisomer 21) obtained by reaction with diazomethane.

EXAMPLE 54 Preparation of2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid N,N,N',N'-tetraethyl amide

A mixture of2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester (9.36 g, 25 mmol), diethylamine (25 ml) and of water(20 ml) was kept, under stirring, at room temperature for 15 hours. Thesolvents were removed by evaporation at room temperature under reducedpressure.

Diethylether (50 ml) was added to the residue and the mixture wasrefluxed for 1 hour; then it was cooled at room temperature, filteredand the filtrate was dried under reduced pressure.2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid N,N,N',N'-tetraethyl amide (11 g, 24 mmol; yield 96%) was soobtained.

M.p.=108°-112° C.

¹ H-NMR (200 MHz, CDCl₃ -TMS) delta (ppm): 0.83(t, 3H, J=7 Hz); 1.11(t,12H, J=7 Hz); 2.00(q, 2H, J=7 Hz); 2.79(q, 8H, J=7 Hz); 3.83(s, 3H);4.32(2H, ABq, Δν=17.8, J=8 Hz); 6.9-7.8(6H, aromatic protons).

IR (Nujol): 1605, 1630 (stretching C=O)

EXAMPLE 55 Preparation of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid N,N,N',N'-tetramethyl amide

A mixture of the two diastereoisomers of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester 3 and 4 in ratio 3:4=9:1 (6.65 g, 12.5 mmol),diethylamine (27.5 ml) and of water (20 ml) was kept, under stirring, atroom temperature for 15 hours. The solvents were removed under reducedpressure. Diethylether (50 ml) was added to the residue. The insolublewas filtered, washed with diethylether, and dried under reducedpressure. The diastereoisomeric mixture of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid N,N,N',N'-tetraethyl amide 24 and 25 (6.75 g, 11 mmol; yield 88%),in ratio 24:25=9:1 (determined by ¹ H-NMR, 200 MHz)

¹ H-NMR (200 MHz, CDCl₃ -TMS) delta (ppm): diastereoisomer 24 (RRS):1.06(t, 12H, J=7 Hz); 1.69(d, 3H, J=7 Hz); 2.76(q, 8H, J=8 Hz); 4.00(s,3H); 4.55(2H, ABq, Δν=35.1, J=8 Hz); 4.54(q, 2H, J=7 Hz); 7.2-8.2(5H,aromatic protons).

EXAMPLE 56 Preparation of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid disodium salt

A mixture of the two diastereoisomers of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester 3 and 4 in ratio 3:4=9:1 (6.65 g, 12.5 mmol), sodiumhydroxyde (1 g, 25 mmol), dimethoxyethane (10 ml), and of water (10 ml)was kept, under stirring, at room temperature for 2 hours. The reactionmixture was diluted with water and extracted with diethylether. Theaqueous phase was concentrated under reduced pressure to give thediastereoisomeric mixture of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid disodium salt 26 and 27 (11.5 mmol; yield 92%) in ratio 26:27=9:1(determined by ¹ H-NMR 200 MHz).

EXAMPLE 57 Preparation of(+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid from adiastereoisomeric mixture of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid 7 and 8 in ratio 7:8=93:7

A mixture of the two diastereoisomers of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphtyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid 7 and 8 in ratio 7:8=93:7 (9.3 g, 18.45 mmol) and of an aqueoussolution (110 ml) prepared by dissolving K₂ HPO₄ (26.1 g) and KH₂ PO₄(5.7 g) in water (384 ml) was heated, under stirring, at 100° C. for 21hours. The reaction mixture was cooled at room temperature (pH 4.2),acidified with conc HCl to pH 1, and extracted with diethylether (3×100ml). The combined organic extracts were washed with water and dried oversodium sulfate. Evaporation of the solvent under reduced pressure gave aresidue that on the basis of the GLC analysis carried out on a sampletreated with diazomethane was constituted of2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (4.33 g, 14.02 mmol;yield 76%) and of the starting diastereoisomer 7 (1.3 g).

Purification by column chromatography of the reaction crude (silica gel;eluent hexane:diethylether=7:3) gave the pure(+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (4.22 g, 13.66mmol; yield 74%) in 97% enantiomeric excess.

M.p.=168°-170° C.

[α]_(D) ²⁰ =+40.8° (c=0.5%, chloroform)

HPLC analysis, carried out as described in J. Pharm. Sci. 68, 112(1979), showed an enantiomeric ratio S(+):R(-)=98.5:1.5. Theenantiomeric ratio was confirmed by ¹ H-NMR 200 MHz analysis carried outin CDCl₃ using an optically active shifting agent (europium (III)tris-[3-(eptafluoropropylhydroxymethylene)-d-camphorate]) on thecorresponding methyl ester obtained by treating a sample of acid withdiazomethane.

EXAMPLE 58

A mixture of the two diastereoisomers of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid 7 and 8 in ratio 7:8=93:7 (2.27 g, 4.5 mmol) and of an aqueoussolution (31.5 ml) prepared dissolving K₂ HPO₄ (26.1 g) and KH₂ PO₄ (5.7g) in water (384 ml) was heated, under stirring, at 100° C. for 42hours. The reaction mixture was cooled at room temperature (pH 4.2) andworked up as described in example 57.(+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (1.32 g, 4.2mmol; yield 93%) was obtained in 97% enantiomeric excess. Theenantiomeric ratio S(+):R(-)=98.5:1.5 was confirmed by HPLC and by ¹H-NMR analysis carried out as described in example 57.

EXAMPLE 59 Preparation of the pure2-(1(S)-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid (diastereoisomer7)

A mixture of the two diastereoisomers of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid 7 and 8 in ratio 7(RRS):8(RRR)=94:6 (134.42 g, 0.266 mol) and of anaqueous solution (1726 ml) prepared dissolving K₂ HPO₄ (174 g) and KH₂PO₄ (38 g) in water (2000 ml) was heated, under stirring, at 90° C. for14 hours. The reaction mixture was cooled at room temperature (acidicpH), acidified with conc HCl to pH 1, and extracted with diethylether(3×150 ml). The combined organic extracts were washed with water andanhydrified over sodium sulfate. Evaporation of the solvent underreduced pressure gave a residue that was dried under vacuo at 80° C. for12 hours. A solution of methanesulfonic acid (1 ml) in methanol (2000ml) was added to the residue (118 g) so obtained. The solution washeated at reflux for 2 hours, cooled at room temperature, neutralizedwith sodium bicarbonate. The solvent was removed under reduced pressureand water (1000 ml) was added to the residue. The solution was extractedwith diethylether (2×500 ml). The combined organic extracts were washedwith water, dried over sodium sulfate, and cncentrated in vacuo.Purification of the residue by column chromatography (silica gel; eluenthexane:diethylether=8:2) gave the pure2-(1(S)-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester 3 (56 g, 0.105 mol).

A solution of sodium hydroxyde (5.32 g, 0.133 mol) in water (70 ml) wasadded dropwise in 1 hour, under stirring, to a solution of thediastereoisomer 3 (35.4 g, 0.0665 mol) in methanol (250 ml) at 20° C.The reaction mixture was kept at 20° C. for 2 hours; then methanol wasremoved under reduced pressure mantaining the initial volume of thesolution by addition of water. The aqueous solution, so obtained, wasextracted with dichloromethane, acidified with conc HCl to pH 1, andextracted with diethylether (3×100 ml). The combined organic extractswere washed with water, anhydrified over sodium sulfate, filtered, andconcentrated in vacuo. Crystallization of the residue fromdichloromethane gave the pure2-(1(S)-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid (diastereoisomer 7).

M.p.=184°-186° C.

[α]_(D) ²⁰ =+39.73° (c=1%, acetone)

¹ H-NMR (200 MHz, esadeuteroacetone-TMS) delta (ppm): 1.68(d, 3H, J=7Hz); 4.03(s, 3H); 4.66(q, 1H, J=7 Hz); 4.95(2H, ABq, Δν=34.67 Hz, J=6.5Hz); 7.46-8.18(m, 5H, aromatic protons).

EXAMPLE 60 Preparation of (+)-2(S)-[4-(2-methylpropyl)-phenyl]propionicacid

A mixture of the two diastereoisomers of2-(1-bromoethyl)-2-[4-(2-methylpropyl)-phenyl]-1,3-dioxolane-4(R),5(R)-dicarboxylicacid 13 and 14 in ratio 13:14=87:13 (3.29 g, 8.2 mmol) was added to anaqueous solution (49 ml) of K₂ HPO₄ (4.26 g) and KH₂ PO₄ (0.93 g). Thesolution (pH 6.6) was heated, under stirring, at 100° C. for 68 hours.The reaction mixture was cooled at room temperature (pH 5.5), dilutedwith water (100 ml), acidified with con HCl to pH 1, and extracted withdiethylether (3×40 ml). The organic phase was then extracted with a 10%aqueous solution of sodium bicarbonate (6×40 ml). The combined aqueousextracts were acidified with conc HCl to pH 1 and extracted withdiethylether (3×50 ml). The combine organic extracts were washed withwater, dried over sodium sulfate, and concentrated in vacuo.Purification by column chromatography (silica gel; eluenthexane:diethylether=8:2) gave the pure2[4-(2-methylpropyl)-phenyl]-propionic acid (0.28 g).

[α]_(D) ²⁰ =+47.9° (c=1%, ethanol 95%)

EXAMPLE 61

A mixture of the two diastereoisomer of2-(1-bromoethyl)-2-[4-(2-methylpropyl)-phenyl]-1,3-dioxolane-4(R),5(R)-dicarboxylicacid 13 and 14 in ratio 13:14=87:13 (3.29 g, 8.2 mmol) was added to anaqueous solution (115 ml) of KH₂ PO₄ (16.4 g) and NaOH (0.82 g). Thesolution (pH 5) was heated, under stirring, at 100° C. for 90 hours.

The reaction mixture was cooled at room temperature (pH 3.5) and workedup as described in example 60.

Pure 2-[4-(2-methylpropyl)-phenyl]-propionic acid (0.66 g) was obtained.

[α]_(D) ²⁰ =+48.8° (c=1%, ethanol 95%)

EXAMPLE 62

A mixture of the two diastereoisomers of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid 7 and 8 in ratio 7:8=94:6 (2.52 g, 5 mmol) was added to an aqueoussolution (70 ml) of KH₂ PO₄ (10 g) and NaOH (1.4 g). The solution (pH 6)was heated at 90° C. for 50 hours. The reaction mixture was cooled atroom temperature (pH 6.0) and worked up as described in example 57.

Pure (+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (1.3 g, 4.2mmol; yield 84%) was obtained in 90% enantiomeric excess.

M.p.=168°-170° C.

[α]_(D) ²⁰ =+37.85° (c=0.5%, chloroform)

The enantiomeric ratio S(+):R(-)=95:5 was confirmed by HPLC and by ¹H-NMR analysis carried out as described in example 57.

EXAMPLE 63

The pure diastereoisomer2-(1(S)-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid 7 (2.52 g, 5 mmol) was added to an aqueous solution (70 ml) of KH₂PO₄ (10 g) and NaOH (1.4 g). The solution (pH 6) was heated at 90° C.for 50 hours. The reaction mixture was cooled at room temperature (pH5.9) and worked up as described in example 57. Pure(+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (1.02 g, 3.3mmol; yield 66%) was obtained in 98% enantiomeric excess.

M.p.=168°-170° C.

[α]_(D) ²⁰ =+40.74° (c=50%, chloroform)

The enantiomeric ratio S(+):R(-)=99:1 was confirmed by HPLC and by ¹H-NMR carried out as described in example 57.

EXAMPLE 64

Comparative example at pH higher than 7. The pure diastereoisomer 7(RRS)(2.52 g, 5 mmol) was added to an aqueous solution (70 ml) of KH₂ PO₄ (10g) and NaOH (2.5 g). The solution (pH 7.2) was heated at 90° C. for 50hours. The reaction mixture was cooled at room temperature (pH 7.0) andworked up as described in example 57.

Pure (+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (0.88 g,2.85 mmol; yield 57%) was obtained in 78% enatiomeric excess.

M.p.=166°-168° C.

[α]_(D) ²⁰ =+32.58° (c=0.5%, chloroform)

The enantiomeric ratio S(+):R(-)=89:11 was confirmed by HPLC and by ¹H-NMR as described in example 57.

EXAMPLE 65

Comparative example at pH higher than 7.5. The pure diastereoisomer7(RRS) (2.52 g, 5 mmol) was added to an aqueous solution (70 ml) of KH₂PO₄ (10 g) and NaOH (3 g). The solution (pH 7.65) was heated at 90° C.for 50 hours. The reaction mixture was cooled at room temperature (pH7.5) and worked up as described in example 57.

Pure (+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (1.03 g,3.33 mmol; yield 67%) was obtained in 74% enatiomeric excess.

M.p.=164°-168° C.

[α]_(D) ²⁰ =+31.20° (c=0.5%, chloroform)

The enantiomeric ratio S(+):R(-)=87:13 was confirmed by HPLC and by ¹H-NMR as described in example 57.

EXAMPLE 66

A mixture of the two diastereoisomers 7(RRS) and 8(RRR) in ratio7:8=94:6 (2.52 g, 5 mmol) was added to an aqueous solution (70 ml) ofKH₂ PO₄ (10 g) and NaOH (0.5 g).

The solution (pH 5.1) was heated at 90° C. for 52 hours. The reactionmixture was cooled at room temperature (pH 4.2) and worked up asdescribed in example 57.

Optically pure (+)-2(S)-(5-bromo-6-methoxy-2-naphtyl)-propionic acid(1.27 g, 4.11 mmol; yield 82%) was obtained.

M.p.=167°-169° C.

[α]_(D) ²⁰ =+42.2° (c=0.5%, chloroform)

The optical purity was confirmed by HPLC and by ¹ H-NMR as described inexample 57.

EXAMPLE 67

The pure diastereoisomer 7(RRS) (2.52 g, 5 mmol) was added to an aqueoussolution (70 ml) of KH₂ PO₄ (10 g) and NaOH (0.5 g). The solution (pH5.15) was heated at 90° C. for 52 hours. The reaction mixture was cooledat room temperature (pH 4.2) and worked up as described in example 57.

Optically pure (+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid(1.30 g, 4.20 mmol; yield 84%) was obtained.

M.p.=168°-170° C.

[α]_(D) ²⁰ =+42.2° (c=0.5%, chloroform)

The optical purity was confirmed by HPLC and by ¹ H-NMR as described inexample 57.

EXAMPLE 68

The pure diastereoisomer 7(RRS) (2.52 g, 5 mmol) was added to an aqueoussolution (35 ml) prepared dissolving KH₂ PO₄ (26.1 g) and KH₂ PO₄ (5.7g) in water (384 ml).

The solution was heated at 100° C. for 45 hours. The reaction mixturewas cooled at room temperature (pH 4.1) and worked up as described inexample 57.

Optically pure (+)-2(S)-(5-bromo-6-methoxy-2-naphtyl)-propionic acid(1.3 g, 4.2 mmol; yield 84%) was obtained.

M.p.=168°-170° C.

[α]_(D) ²⁰ =+42.23° (c=0.5%, chloroform)

The optical purity was confirmed by HPLC and by ¹ H-NMR as described inexample 57.

EXAMPLE 69

A mixture of the two diastereoisomers 7(RRS) and 8(RRR) in ratio7:8=93:7 (2.52 g, 5 mmol) was added to an aqueous solution (70 ml) ofKH₂ PO₄ (10 g).

The solution (pH 4.2) was heated at 90° C. for 50 hours. The reactionmixture was cooled at room temperature (pH 3.2) and worked up asdescribed in example 57.

Pure (+)-2(S)-(5-bromo-6-methoxy-2-naphtyl)-propionic acid (0.65 g, 2.10mmol; yield 42%) was obtained in 94% enantiomeric excess.

M.p.=164°-165° C.

[α]_(D) ²⁰ =+40.08° (c=0.5%, chloroform)

The enantiomeric ratio S(+):R(-)=97:3 was confirmed by HPLC and by ¹H-NMR as described in example 57.

EXAMPLE 70

A solution of the two diastereoisomers of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid N,N,N',N'-tetraethyl amide 24(RRS) and 25(RRR) in ratio 24:25=9:1(2.93 g, 5 mmol) in water (70 ml) was heated at 90° C. for 50 hours. Thereaction mixture was cooled at room temperature (pH 5.6) and worked upas described in example 57.

Pure (+)-2(S)-(5-bromo-6-methoxy-2-naphtyl)-propionic acid (0.58 g) wasobtained in 96% enantiomeric excess.

M.p.=164°-165° C.

[α]_(D) ²⁰ =+41.74° (c=0.5%, chloroform)

The enantiomeric ratio S(+):R(-)=99:1 was confirmed by HPLC and by ¹H-NMR as described in example 57.

EXAMPLE 71

A mixture of the two diastereoisomers of2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid N,N,N',N'-tetrethyl amide 24(RRS) and 25(RRR) in ratio 24:25=9:1(2.93 g, 5 mmol) was added to an aqueous solution (70 ml) of KH₂ PO₄ (10g) and NaOH (0.5 g).

The solution (pH 5.7) was heated at 90° C. for 50 hours. The reactionmixture was cooled at room temperature (pH 4.2) and worked up asdescribed in example 57.

Pure (+)-2(S)-(5-bromo-6-methoxy-2-naphtyl)-propionic acid (0.54 g) wasobtained in 98% enantiomeric excess.

M.p.=166°-168° C.

[α]_(D) ²⁰ =+41.86° (c=5%, chloroform)

The enantiomeric ratio S(+):R(-)=99:1 was confirmed by HPLC and by ¹H-NMR as described in example 57.

What is claimed is:
 1. An optically active alpha-halogen-ketal havingthe formula: ##STR10## wherein Ar represents phenyl, diphenyl ornaphthyl, unsubstituted or substituted by halogen, C₁ -C₄ alkyl, C₃ -C₆cycloalkyl, benzyl, hydroxy, C₁ -C₄ alkoxy, C₁ -C₄ alkylthio, C₁ -C₄haloalkyl, C₁ -C₄ haloalkoxy, phenoxy, thienylcarbonyl or benzoyl;Rrepresents linear or branch C₁ -C₄ alkyl; R₁ and R₂, each independently,represent hydroxy, O⁻ M⁺, OR₃ or NR₄ R₅, R₃ represents C₁ -C₂₄ alkyl, C₃-C₆ cycloalkyl, phenyl or benzyl, M is the cation of an alkaline metal,R₄ and R₅, each independently, represent hydrogen, C₁ -C₄ alkyl, C₅ -C₆cycloalkyl or --(CH₂)_(n) --CH₂ OH wherein n is 1, 2 or 3, or R₄ and R₅together constitute a --(CH₂)_(m) -- group wherein m is 4 or 5, or --CH₂--CH₂ --R₇ --CH₂ --CH₂ -- group wherein R₇ is oxygen, NH or N(C₁ -C₄)alkyl, and X represents hydrogen, chlorine, bromine or iodine, thecarbon atoms indicated by an asterisk having both (R) or (S)configuration.
 2. The optically active alpha-halogen-ketal of claim 1herein R₁ and R₂ are other than hydroxy.
 3. The optically activealpha-halogen-ketal of claim 1 wherein Ar represents 4-isobutyl-phenyl,3-phenoxy-phenyl, 2-fluoro-4-diphenyl, 4'-fluoro-4-diphenyl,4-(2-thienylcarbonyl)phenyl, 6-methoxy-2-naphthyl,5-chloro-6-methoxy-2-naphthyl, 4-chlorophenyl, 4-difluoromethoxy phenyl,6-hydroxy-2-naphthyl or 5-bromo-6-hydroxy-2-naphthyl.
 4. The opticallyactive alpha-halogen-ketal of claim 1 having the formula: ##STR11##wherein, R₁, R₂ and X have the meanings given in claim 1 for formula(A),Y represents hydrogen or bromine and Z represents hydrogen, methylor an alkaline metal. 5.2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylicacid dimethyl ester.